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Simple Summary: Chimeric Antigen Receptor T-cell (CAR T) therapy has become the preferable therapeutic approach in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Detection of CAR Ts in peripheral blood smear (PBS) is challenging due to the low sensitivity of current morphological technologies. We provide herein a morphological analysis of CAR Ts during the production process and in consecutive PBS obtained from DLBCL patients undergoing CAR T therapy, employing a novel, highly sensitive microscopy platform. We found that activated morphology was attributed predominantly to transduced cells following engagement with target cells. The average number of day 5 CAR Ts, and their sustained presence, were significantly higher in patients obtaining complete response. Also, a high number of CAR Ts was associated with longer cytokine storm release syndrome. These data indicate that CAR T morphological surveillance in PB might serve as a simple, fast and inexpensive method to provide clinically relevant insights. Chimeric Antigen Receptor T-cell (CAR T) therapy has become the preferable treatment in relapsed/refractory diffuse large B-cell lymphomas (DLBCL) patients. Detection of CAR Ts in peripheral blood smear (PBS) is challenging due to insufficient data regarding their morphology and low sensitivity. The morphological evolution of CAR Ts along their production process, and in patients, was established by Full-Field Morphology (FFM), a novel digital microscopy approach that provides highly sensitive PBS analysis. At day 8 of production, 42.7 ± 10.8% of the CAR T transduced cells exhibited activated morphology compared with 9.3 ± 3.8% in untransduced cells. Moreover, engagement of transduced CAR Ts with target cells resulted in further morphological transformation into activated morphology (83 ± 5.6% of the cells). In patients, the average number of day 5 CAR Ts, and their sustained presence, were significantly higher in patients obtaining complete response. A high number of activated morphology CAR Ts at day 14 was associated with prolonged cytokine release storm. Overall, CAR Ts exhibited heterogeneous morphology, with the activated morphology attributed predominantly to transduced cells following engagement with target cells. Post-transfusion CAR T detection was associated with increased complete responses. FFM CAR T surveillance in PBS may serve as a simple inexpensive method to provide clinically relevant insights into this treatment modality. [ABSTRACT FROM AUTHOR]

Simple Summary: Double/triple-hit lymphomas (DHLs/THLs) are an aggressive type of high-grade B-cell lymphomas (HGBLs), characterized by translocations in MYC and BCL2/BCL6. DHL patients respond poorly to standard chemoimmunotherapy regimens; thus, timely and accurate diagnosis is of paramount importance for their proper clinical management. The standard technique used for the identification of these translocations is fluorescence in situ hybridization (FISH), which is not routinely performed at every medical center to all potential patients. In the current study, we employed an image-based, artificial intelligence, deep learning algorithmic tool for the identification of DHL/THL cases by analyzing scanned histopathological H&E-stained tissue slide images. Our preliminary results demonstrate high performances, suggesting the potential use of such a solution in the clinical workflow to support the management of HGBL patients. Deep learning applications are emerging as promising new tools that can support the diagnosis and classification of different cancer types. While such solutions hold great potential for hematological malignancies, there have been limited studies describing the use of such applications in this field. The rapid diagnosis of double/triple-hit lymphomas (DHLs/THLs) involving MYC, BCL2 and/or BCL6 rearrangements is obligatory for optimal patient care. Here, we present a novel deep learning tool for diagnosing DHLs/THLs directly from scanned images of biopsy slides. A total of 57 biopsies, including 32 in a training set (including five DH lymphoma cases) and 25 in a validation set (including 10 DH/TH cases), were included. The DHL-classifier demonstrated a sensitivity of 100%, a specificity of 87% and an AUC of 0.95, with only two false positive cases, compared to FISH. The DHL-classifier showed a 92% predictive value as a screening tool for performing conventional FISH analysis, over-performing currently used criteria. The work presented here provides the proof of concept for the potential use of an AI tool for the identification of DH/TH events. However, more extensive follow-up studies are required to assess the robustness of this tool and achieve high performances in a diverse population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The risk of developing non-Hodgkin lymphoma increases with age, yet elderly patients are under-represented in clinical trials. Here, we evaluate a combination regimen including ifosfamide, carboplatin and etoposide with or without rituximab (ICE ± R) in 32 fit elderly patients (median age 75.6 years) with relapsed or refractory diffuse large B-cell lymphoma. ICE ± R was generally administered in reduced doses and was well tolerated. The overall response rate (ORR) was 53.1% with a complete response (CR) rate of 40.6%. The median progression free survival (PFS) and overall survival (OS) were 3.9 and 17.0 months, respectively. Patients who responded to ICE ± R achieved median PFS of 47.2 months and OS of 78.9 months. Patients ineligible for autologous transplantation who responded to ICE ± R were treated with additional cycles, and achieved a median PFS of 18.9 months and OS of 21.7 months. Previous response to first-line therapy was the strongest predictor of response, PFS and OS to second-line treatment. [ABSTRACT FROM AUTHOR]