Cell Lymphoma Patients Research Articles

Blocking the CD47-Sirpa Axis Enhances Tafasitamab-Mediated Phagocytosis

Introduction Around 40% of diffuse large B cell lymphoma (DLBCL) patients have refractory disease or experience relapse, thus highlighting the need for novel, more effective therapies (Coiffier et al). The immunotherapy Tafasitamab (MOR208) is an Fc-modified, humanized, monoclonal anti-CD19 antibody approved in combination with lenalidomide as a second line of therapy for R/R DLBCL. Tafasitamab mediates its therapeutic effect directly or via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Macrophages represent a key component of the DLBCL microenvironment and are critical effectors of antibody therapies (Uchida et al). However, ADCP is reportedly counteracted by increased expression of the immune checkpoint molecule CD47 on lymphoma targets (Chao et al). In addition, the inhibitory receptor of CD47, signal regulatory protein alpha (SIRPα) is increased on macrophages from patients with follicular lymphoma who relapse or progress after frontline lenalidomide and rituximab (Marques-Piubelli et al). Aim of the study The current study investigates the impact of the CD47-SIRPα axis on tafasitamab-mediated phagocytosis and the potential of concomitant treatment with an anti-CD47 blocking antibody to improve its efficacy. Results We show that both, CD47 and its inhibitory receptor SIRPa were elevated in lymph node biopsies from DLBCL patients. CD47 expression was evaluated in 6 DLBCL patients and 5 healthy controls and SIRPα was evaluated in 9 patients and 7 controls. In fact, increased expression of SIRPa on macrophages correlated with decreased ADCP activity of tafasitamab, and CRISPR-mediated CD47 overexpression on lymphoma targets impaired tafasitamab-mediated phagocytosis, in vitro. Combination of tafasitamab and an anti-CD47 blocking antibody enhanced ADCP activity of in vitro generated macrophages. Furthermore, lymphoma cells with low CD19 expression were efficiently eliminated by the combination therapy. Importantly, the combination enhanced tafasitamab-mediated phagocytosis of primary DLBCL cells using primary, patient-derived lymphoma-associated macrophages (LAMs) as effectors, in an autologous setting. Conclusion Our results show increased expression of CD47-SIRPa axis in primary DLBCL samples and indicate that CD47 blockade can enhance the phagocytic potential of tumor-targeting immunotherapies such as tafasitamab. Our findings suggest that there is merit in exploring the clinical utility of combining tafasitamab with an anti-CD47 blocking antibody in lymphoma. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of DLBCL Patients Achieving Complete Remission after R-ICE Chemoimmunotherapy

Introduction Diffuse large B cell lymphoma (DLBCL) patients who are refractory or relapse (r/r) within 12 months of completion of initial therapy (refractory and early relapse, RER) have inferior outcomes than those relapsing 12 months or after (late relapse, LR). Recent trials of anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy have demonstrated improved event-free survival (EFS) in RER-DLBCL when compared with standard chemotherapy with intent to undergo autologous stem cell transplant (ASCT). Due to clinical urgency and logistic factors many patients with r/r DLBCL will receive second line systemic chemotherapy. The optimal treatment for those responding to second line therapy is not yet well defined. Methods We conducted an IRB approved retrospective review of r/r DLBCL patients treated with rituximab, ifosfamide, carboplatin, etoposide (R-ICE) at three academic medical centers between 2010-2020. Baseline characteristics and outcomes were collected from the electronic medical record. Patients having RER-DLBCL were defined as those who had disease that was r/r within 12 months of the end of initial therapy. Outcomes evaluated included disease response to initial and second line therapy, subsequent ASCT and CAR T cell therapy, progression free survival (PFS) and overall survival (OS). Response was assigned by CT scan in 38 (13%) and by PET in 236 (81%) of patients. All analyses were done using R and its packages. Results We identified 291 patients treated with R-ICE for r/r DLBCL, 182 (62.5%) of whom had RER-DLBCL and 109 (37.4%) and LR-DLBCL. Baseline characteristics between RER and LR-DLBCL were comparable (Table 1), with the exception of age. RER-DLBCL patients received a median of 2 cycles vs. 3 cycles of RICE for LR-DLBCL (p = 0.008). Patients with RER-DLBCL had overall (OR) and complete response (CR) rates of 62% and 30%, vs. 86% and 45% among patients with LR-DLBCL, respectively (p < 0.0001). 170 patients underwent ASCT. 79 patients received CAR T cell therapy, 42 (14%) without prior ASCT and 37 (13%) after ASCT. After a median follow up of 53 months (IQR, 36-76), median PFS for ER-DLBCL vs. LR-DLPBCL was 6 months vs. 31 months (HR=1.84 [95%CI 1.36-2.49, p < 0.001), with 4-year PFS estimates of 24% (95% CI 18-32%) vs. 40% (95% CI 31-51%), respectively. Median OS was 36 months for ER-DLBCL vs. 68 months for LP-DLBCL (HR=1.63 [95% CI 1.13-2.36], p = 0.009), with 4-year estimates of 48% (95% CI 40-56%) vs. 66% (95% CI 57-76%), respectively. Among patients achieving CR after R-ICE, median PFS was 43 months for RER-DLBCL vs. not reached for LR-DLBCL (HR=1.43 [95% CI 0.8-2.4], p = 0.2) (Figure 1), with 4-year PFS estimates of 43% (95% CI 31 - 60%) and 50% (95% CI 37 - 68%), respectively. Median OS for patients in CR after R-ICE was 85 months for RER-DLBCL and 102 months for LR-DLBCL (HR = 0.98 [95% CI 0.5 - 1.92], p > 0.9), with 4-year OS estimates of 69% (95% CI 57 - 84%) and 72% (95% CI 60 - 87%), respectively. Patients who underwent ASCT after achieving CR had median PFS of 71 months (95% CI 29 - NR), while median survival was not reached (95% CI 85 months - NR). Four-year PFS and OS estimates of 53% and 77%, respectively. Among patients undergoing ASCT after CR, there was no statistically significant difference in PFS (4-year PFS: RER-DLBCL 48.5% vs. LR-DLBCL 58.6%, p = 0.1) or OS (4-year OS: RER-DLBCL 78.2% vs. LR-DLBCL 74.9%, p = 0.9) On univariate analysis, elevated LDH, RER-DLBCL and failure to achieve CR after R-ICE (i.e. PR or SD/PD) were associated with increased hazards of progression, while age > 70 years, elevated LDH, RER-DLBCL and failure to achieve CR were associated with increased hazards of death (Table 1). On multivariate analysis, however, the effect of early relapse was not statistically significant for risk of progression or death, whereas response to R-ICE retained statistical significance. Conclusions The poor outcomes of RER-DLBCL are the result of a high proportion of patients with chemorefractory disease. However, DLBCL patients who achieve CR after R-ICE salvage can achieve long term disease control, regardless of the time to relapse from initial therapy, in particular if they proceed to ASCT. These results suggest second line chemotherapy, followed by ASCT vs. CAR T for chemosensitive and chemorefractory patients may be a response - adapted approach that can maximize DLBCL patient outcomes, regardless of time to relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Exhausted T Cells Characterized By Upregulation of Specific Transcription Factors Are Increased in a Mouse Model of De Novo Mature B Cell Neoplasms

Introduction: Recent studies demonstrated that exhausted T cells expressing immune checkpoint molecules such as PD-1, Tim-3, and TIGIT are increased at tumor sites in diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM) patients. However, the pathogenetic significance of exhausted T cells remains controversial and needs thorough investigation. Method: In this study, we used a mouse model with human MM mutations of conditional Utx loss and BrafV600E expression only in mature B cells, which developed mature B cell neoplasms de novo with time. Therefore, we expected this mouse model to show immune escape similar to human patients, rather than the currently available transplanted mouse models. To examine the level of T cell exhaustion, we analyzed the expression of PD-1 and Tim-3 on CD8+ T cells. To understand the characteristics of exhausted T cells, we performed flow cytometry (FCM) and RNA-seq analyses. Result: In mice with mature B cell neoplasms, PD-1+ Tim-3+ and PD-1+ Tim-3- T cells were significantly increased in BM, spleen, and lymph nodes, compared with control mice (p<0.0001). The expression level of TIGIT, which was reported to be expressed on CD8+ T cells of MM patients more frequently than other inhibitory receptors, was significantly higher in PD-1+ Tim-3+ T cells. These data suggest that the increase in PD-1+ Tim-3+ and PD-1+ Tim-3- T cells at the tumor site may be related to the tumor pathogenesis in our mouse model. We then investigated the functional and transcriptional features of these exhausted T cells. The FCM analyses revealed that PD-1+ Tim-3+ T cells had the highest production capacity of granzyme B and expressed the highest level of Ki-67 and annexin V, compared with PD-1+ Tim-3- and PD-1- Tim-3- T cells. These characteristics are consistent with those of terminally exhausted T cells previously reported. RNA-seq analyses also revealed the similarities between PD-1+ Tim-3+ T cells in this mouse model and terminally exhausted T cells. The transcription factors Tox and Nr4a2, which reportedly contribute to the progression of T cell exhaustion, were up-regulated in PD-1+ Tim-3+ T cells. On the other hand, PD-1+ Tim-3- T cells showed high production capacity of IFN-γ and TNF-α and expressed moderate levels of Ki-67 with less apoptotic features. RNA-seq demonstrated the enrichment of gene sets related to immune system process. Tox and Nr4a2 were also up-regulated in PD-1+ Tim-3- T cells but their levels were lower than in PD-1+ Tim-3+ T cells. Furthermore, PD-1+ Tim-3- T cells retained the expression of Tcf7, encoding TCF-1 which plays a significant role in maintaining stem-like features. These results indicate that PD-1+ Tim-3+ T cells have direct cytotoxicity and strong proliferative capacity, however most of these cells are severely apoptotic. Therefore, PD-1+ Tim-3+ T cells are possibly unable to keep long-term anti-tumor functions. In contrast, PD-1+ Tim-3- T cells show immunological responsiveness and progenitor-like transcriptional features, suggesting that these cells may maintain effective immune functions for a long time. When we stimulated CD8+ T cells in vitro in the presence or absence of lenalidomide or pomalidomide, these IMiDs down-regulated the expression of Tox and Nr4a2, suggesting that they might prevent T cell exhaustion. Conclusion: The present study using our mouse model revealed the heterogeneity and the increase in exhausted T cells during the development of de novo mature B cell neoplasms. PD-1+ Tim-3+ T cells exhibit terminally exhausted features, whereas PD-1+ Tim-3- T cells retain stem-like transcriptional features. IMiDs might prevent excessive T cell exhaustion and contribute to the immune response with long-term effects.

Clinical Laboratory Mutation Analysis Performed on Tumor Biopsies from Patients with First Relapsed/Refractory Aggressive B Cell Lymphoma Treated with Curative-Intent Immunochemotherapy

Background Comprehensive genomic analysis has identified subgroups of diffuse large B cell and high grade B cell lymphoma (DLBCL/HGBL) patients (pts) who experience inferior survival outcomes following receipt of first-line treatment (1Ltx) with immunochemotherapy (PMID: 29713087, 29641966). However, this type of analysis has not been performed for pts with R/R DLBCL/HGBL treated with curative-intent IC in the 2L, although descriptive analyses of mutations (mut) present at the time of first R/R DLBCL/HGBL have been reported (PMID: 26647218, ICML 2017 #294). Here we report mut identified by clinical laboratory mutation analysis (CLMA) in tumor biopsies (bx) obtained at the time of first R/R DLBCL/HGBL in patients subsequently receiving 2Ltx with curative-intent IC with analysis of response and survival outcomes. Methods Pts diagnosed with first R/R DLBCL/HGBL after receipt of 1Ltx who underwent tumor bx at that time with diagnostic CLMA performed at the University of Pennsylvania from 2015-21 with one of three lymphoma sequencing panels who were treated with RICE or RDHAP/C as 2Ltx were retrospectively analyzed. Immunohistochemical staining (IHC) for MYC and BCL2 expression as well as fluorescence in situ hybridization (FISH) for MYC, BCL2 and BCL6 rearrangements were performed as per institutional standard. 2Ltx was given at the discretion of the treating physician. Disease free survival (DFS) was defined as the interval between diagnosis of first R/R DLBCL/HGBL to next occurrence of R/R DLBCL/HGBL or last follow-up in remission. Overall survival (OS) was defined as the interval between diagnosis and time of death or last follow-up while alive. Data were censored on 7/1/22. Results CLMA was performed on 28 pt tumor bx with 25 successful assays (89% success rate) and a median result turnaround time (TAT) of 17 days. Baseline clinicopathologic and tx characteristics are listed in the Table and mutations detected by frequency with n≥1 in the Figure. 2Ltx was RICE in 18 (72%) and R-DHAP/C in 7 (28%) pts. With a median follow-up of 32.4 months from the time of first R/R disease, the Kaplan Meier estimate of 2 year (y) DFS was 12% (95% confidence interval [CI] 2-31%) and 2y OS 59% (95% CI 33-78%). Response to 2Ltx was achieved by 18 pts (72%). Additional analysis was performed to determine factors predictive of response to 2Ltx and 2y DFS using the characteristics in Table 1, 2Ltx received as well as mutation detected in ≥5 cases (CREBBP, TP53, SOCS1 and MYD88). Those predictive of response to 2Ltx with P<0.10 on univariate logistic regression were receipt of R-DHAP/DHAC vs RICE (odds ratio [OR] 0.15, 95% CI 0.02-1.0, P=0.06) and CREBBP mutation vs not (OR 0.07, 95% CI 0.01-0.83, P=0.04). Those predictive of disease relapse by 2y with P<0.10 on univariate Cox regression were HGBL vs DLBCL histology (hazard ratio [HR] 4.8, 95% CI 1.4-16.4, P=0.01), receipt of R-DHAP/DHAC vs RICE (HR 4.7, 95% CI 1.6-13.8, P=0.005), GCB vs non-GCB cell of origin (HR 1.9, 95% CI 0.94-4.0, P=0.07), MYC rearrangement vs not (HR 4.5, 95% CI 1.3-15.4, P=0.02) and double hit lymphoma vs not (HR 3.8, 95% CI 1.0-14.5, P=0.046). Meaningful multivariate analyses for response to 2Ltx or disease relapse at 2y could not be carried out due to small sample size. Conclusion In this cohort of pts with DLBCL/HGBL whose tumor bx obtained at the time of first R/R disease underwent CLMA and were treated with RICE or RDHAP/C as 2Ltx, few patients achieved long-term DFS in spite of a high rate of chemosensitivity to 2Ltx. Mut in CREBBP predicted for a lower response rate to 2Ltx but not disease progression at 2y, and no other mut analyzed predicted for either outcome. Given the low rate of 2y DFS as well as a shift in practice to the use of chimeric antigen receptor-modified T cells (CART) as 2Ltx for pts with early R/R DLBCL/HGBL, these data do not support further investigation of CLMA performed on a larger sample of tumor bx from all pts at the time of first R/R disease who are candidates for CART. However, performance of CLMA could further explored in the subset of DLBCL/HGBL pts with late first R/R disease for whom the standard of care 2Ltx remains curative-intent IC, as the presence of absence of mut predicting for disease response/DFS in this pt population may inform tx decisions given the availability of non-cytotoxic agents as 2L tx as well as CART at the time of subsequent R/R disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Polatuzumab Vedotin in Combination with Rituximab Plus Bendamustine in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Single Center Analysis of Pola Compassionate Use Program (CUP) in China

Objective: To investigate the efficacy and safety of Polatuzumab vedotin+rituximab±bendamustine (Pola-(B)R) in relapse/refractory diffuse large B cell lymphoma (R/RDLBCL) patients. Methods: The clinical data of 13 patients enrolled in Chinese Pola compassionate use program (CUP) in department of Hematology-Oncology of Chongqing University Cancer Hospital from October 2021 to July 2022 were collected. There were 5 males and 8 females, and the median age was 58 years (ranged 45-76 years)of the patients,10 cases received Pola-BR and the other 3 received Pola-R. Before the use of Pola, all patients have received at least 2-8 lines Immunochemotherapy and median treatments were 5 lines. 10 patients (77%) were classified as medium and high-risk group according to IPI or aaIPI Prognostic Scoring. 11 patients (85%) had stage III~IV disease, 8 patients (62%) were Non-GCB types, 7 patients(54%) with Ki-67 over 80% in pathological IHC and 2 patients (15%) were diagnosed as double-expression lymphoma . At data cut off , the objective response rate(ORR) of 13 patients was 46.2%(6/13), no patients reached complete remission(CR) , 5 patients (38.4%) could not complete whole 6 cycles of pola combined treatment for intolerable adverse reactions and 4 patient(30.8%)died due to progression disease(PD). The most common hematological toxicity events were neutrophil count decreased,thrombocytopenia and anemia, with 3-4 level occurrence rate was 38.4%,30.8% and 15.4%. The most common non-hematological toxicity events were peripheral neuropathy, pneumonia and fatigue. 2 patients had tumor lysis syndrome and 1 patient had hemophagocytic syndrome. Conclusions: Polatuzumab is widely used all over the world, even for heavily treated Chinese R/R DLBCL patients, the Pola-(B)R regimen still achieves remission and safety are comprehensive controllable.

Baseline Systemic Inflammatory Markers Interleukin 6 and Ferritin Are Associated with Toxicities and Progression-Free Survival in Multiple Myeloma Patients Treated with Idecabtagene Vicleucel

Introduction: A challenge of chimeric antigen receptor (CAR) T-cell therapy is the en-masse activation of tumor-reactive T-cells that can lead to cardiovascular, respiratory, and neurologic toxicities, including cytokine release syndrome (CRS) and neurotoxicity (NT). Recent studies found that elevated levels of cytokines and inflammatory markers pre-treatment are associated with severe toxicities in B cell lymphoma patients receiving axicabtagene ciloleucel. However, less is known about patients with relapsed/refractory multiple myeloma (RRMM) treated with commercial idecabtagene vicleucel (ide-cel). We evaluated the associations of serum cytokines and inflammatory biomarkers with immune-mediated toxicities and progression-free survival (PFS) in RRMM patients treated with commercial ide-cel. Methods: Serum samples were collected at baseline (within 45 days of lymphodepleting chemotherapy) and daily from infusion until hospital discharge. The Ella automated simple plex immunoassay system (ProteinSimple) was used to measure cytokines including GM-CSF, IL2, IL6, IL15, IFNγ, TNFα, and Angiopoietin 1&2. Standard clinical tests were used to measure ferritin and C-reactive protein at baseline (pre-lymphodepleting chemotherapy), infusion, and daily until hospital discharge. Treatment-related toxicities were graded based on ASTCT guidelines and managed according to institutional policies. Treatment responses were graded based on IMWG response criteria. Chi-square and Kruskal-Wallis tests were used to examine the distribution of each cytokine and inflammatory biomarker at baseline, infusion, and peak (highest level between day one post infusion and last day of hospitalization) by any grade and ≥ grade 2 CRS and NT. For cytokines or inflammatory biomarkers associated with CRS and NT, maximally selected rank statistics were used to determine optimal cut-points for PFS, and Kaplan-Meier survival curves and log-rank tests were used to examine PFS by optimal cut-points of selected cytokines and inflammatory biomarkers. Results: 28 patients who received ide-cel by May 1st, 2022 were included. Median age was 65 years. 38% of patients had high-risk cytogenetics and 54% had penta-refractory disease. Median number of prior lines of therapy was 6 (range 4-13). CRS was seen in 79% (≥ grade 2: 14%) and NT in 11% (≥ grade 2: 7%) of patients. Tocilizumab and steroids were used in 79% and 32% of patients, respectively. With a median follow up of 6.2 months, best overall response rate was 82%, with 57% of patients achieving a complete response or better. Of those, 69% were minimal residual disease negative. Four patients died of myeloma progression. Patients with any grade versus no CRS had higher levels of baseline ferritin (402 vs 133 ng/mL; P=0.045), peak ferritin (2804 vs 191 ng/mL; P<0.001), and peak IL6 (3681 vs 20 pg/mL; P<0.001). Patients with ≥ grade 2 vs < grade 2 CRS had higher levels of baseline IL6 (19 vs 5 pg/mL; P=0.04; Figure 1). A positive but not statistically significant association was observed for baseline IL6 with ≥ grade 2 vs < grade 2 NT (19 vs 6 pg/mL; P=0.12). There were positive correlations between baseline and peak ferritin (r=0.43; P=0.02) and baseline ferritin and IL6 (r=0.58; P=0.005), but no correlation between baseline and peak IL6 (r=-0.06; P=0.8). Using optimal cut-points for baseline ferritin (1700 ng/mL) and IL6 (10 pg/mL), patients with high (n=5) vs low (n=23) baseline ferritin had an inferior PFS (median PFS of 4.8 months vs not reached [NR]; P=0.0005), and patients with high (n=6) vs low (n=16) baseline IL6 had an inferior PFS (median PFS of 3 months vs NR; P=0.069). When combining baseline ferritin and IL6, patients with either high (n=8) vs low (n=20) ferritin or IL6 had an inferior PFS (median PFS of 4.8 months vs NR; P=0.021; Figure 1). No other differences in inflammatory biomarkers or cytokines by toxicities or PFS were identified. Conclusions: In our single center experience, we found associations between ferritin and IL6 with CRS and NT. Median PFS was inferior in patients with elevated baseline ferritin and IL6. This suggests that a pre-existing pro-inflammatory state puts ide-cel patients at risk for toxicities in addition to inferior PFS. Tailoring toxicity and additional therapeutic management to patient risk may mitigate morbidity and mortality. D.K.H. and L.C.P contributed equally; M.A. and M.L.D contributed equallyFigure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sequencing-Based Analysis of Clonal Evolution of 25 Mantle Cell Lymphoma Patients at Diagnosis and after Failure of Standard Immunochemotherapy

Sequencing-Based Analysis of Clonal Evolution of 25 Mantle Cell Lymphoma Patients at Diagnosis and after Failure of Standard Immunochemotherapy

Predictors and Implications of Renal Injury in Large Cell Lymphoma Patients Receiving CD19 CAR T Cell Therapy

Background: Chimeric Antigen Receptor (CAR) T cells directed against CD19 induce durable remissions in patients with relapsed or refractory large cell lymphoma (LBCL), but many patients experience treatment-related toxicity. Cytokine release syndrome (CRS), immune effector cell-associated neurologic syndrome (ICANS), and hematologic toxicity are extensively characterized. However, limited data exist on the burden, predictors, and implications of acute kidney injury (AKI) after CAR T cell therapy. Methods: In this single-center real-world retrospective study, we analyzed baseline (pre-lymphodepletion) and dynamic changes in renal function in adult patients with relapsed or refractory LBCL treated with CD19 CAR T cells. Estimated glomerular filtration rate (eGFR) was calculated via the 2021 CKD-EPI Creatinine Equation. Chronic kidney disease grading was tiered by the Kidney Disease Improving Global Outcomes (KDIGO) definitions. Serum creatinine values from day -5 through day 180 were used to assess AKI, which was defined by KDIGO criteria. Outcomes were measured from the first day of lymphodepletion. For AKI assessment, disease relapse or progression, anticancer treatment after CAR T cells, and death were considered competing events. Results: We included 200 LBCL patients with a median age of 66 (IQR 20-86) that were treated with CD19 CAR T cells (50% axicabtagene ciloleucel, 32% tisagenlecleucel, 18% lisocabtagene maraleucel) between 2016 and 2022. At baseline, most patients (54%) had a normal eGFR (eGFR ≥90 mL/min) followed by grade 2 CKD (eGFR 60-89 mL/min) in 34% and grade 3 CKD (eGFR 30-59 mL/min) in 12%. Patients with decreased renal function were more likely to be older (p < 0.001) and received CAR T cells with a 41BB costimulatory domain (p=0.028). In a cause-specific Cox model, baseline renal dysfunction was associated with an increased risk for severe neutropenia after CAR-T cell infusion (eGFR 60-89 vs. eGFR ≥90 mL/min; HR 1.53 [95% CI, 1.08-2.17]; p = 0.018). Pre-lymphodepletion eGFR was however not associated with overall survival (OS; p = 0.25), progression-free survival (PFS; p = 0.62), CRS grade 2+ (p = 0.34), or ICANS grade 2+ (p = 0.59). The cumulative incidence of day 180 AKI at any grade and grade 2+ AKI was 14% [95% CI 9.3 - 19%] and 4.5% [95% CI 2.2 - 8%], respectively (Figure 1A). At day 180, 14 of 83 (17%) evaluable patients had an eGFR <60. In a univariable cause-specific Cox regression model, baseline lower hemoglobin (p = 0.01) and albumin levels (p < 0.001) and higher ferritin (p = 0.005) and LDH levels (p = 0.05) were associated of AKI; no association was detected with baseline renal function (p = 0.47). Serum albumin remained significant in a multivariable model for AKI (HR 0.17 [95%CI 0.08 - 0.37], p < 0.001; Figure 1B). In a subset of patients with extensive cytokine profiling (n=50), pre-lymphodepletion log transformed IL6 was strongly associated with AKI (HR 3.59 [95% CI 1.19 - 10.8]). Finally, patients who developed any AKI through day 180 had significantly lower PFS (HR 2.13 [95% CI 1.35-3.37]; P=0.001) and OS (HR 2.01 [95% CI 1.22-3.31]; P=0.006). Conclusions: In this largest study to date on renal injury in CAR T patients, we find acute kidney injury as a common complication of CAR-T cell therapy, exceeding 10%. The association between renal injury and subsequent mortality suggests that AKI is a clinically and prognostically significant complication. The discovery that readily available biomarkers reflecting physiological reserve, disease burden, and systemic inflammation inform on renal injury risk may support personalized stratification for risk mitigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune Profiling of Double and Triple Hit High Grade B Cell Lymphoma Patients Treated with DA-EPOCH Reveals Activation of T Cells and Reduced T Cell Exhaustion

Immune Profiling of Double and Triple Hit High Grade B Cell Lymphoma Patients Treated with DA-EPOCH Reveals Activation of T Cells and Reduced T Cell Exhaustion

Abstract 12429: Grade Of CRS is Associated With Cardiac Dysfunction in the Acute Phase, but Do Not Predict the Prognosis of Diffuse Large B Cell Lymphoma Patients Who Underwent CAR-T Therapy

Introduction: As Chimeric Antigen Receptor T cell (CAR-T) therapy gains advantage in the management of diffuse large B cell lymphoma (DLBCL), accumulating evidence shows that it frequently accompanies cardiac dysfunction. Previous retrospective studies indicated the potential involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy, but no prospective study has reported the time course of cardiac dysfunction and its association with prognosis. Purpose: To prospectively examine the sequential changes in cardiac markers over time after CAR-T therapy and to clarify their association between the grade of CRS, cardiac markers, and prognosis. Methods: In this prospective study, 30 DLBCL patients who underwent CAR-T therapy were enrolled. Before and after the treatment, the level of cardiac biomarkers and echocardiographic index were sequentially collected. We classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely Low-CRS group (CRS&lt;2) and High-CRS group (CRS≧2). Cardiac biomarkers, echocardiographic index, and long-term survival prognosis were further analyzed in both groups. Results: The average age of participants was 59.6 years, and 9 (30%) were female. The number of patients in Low- and High-CRS group was 13 and 17, respectively. At the baseline before CAR-T therapy, there were no significant differences in cardiac parameters between two groups. In High-CRS group, NT-proBNP levels were significantly increased on day 3 and 7 compared to the baseline and were significantly higher than Low-CRS group at both timepoints, whereas troponin T level did not show any differences. Likewise, in High-CRS group, GLS was significantly decreased on day 7 and 14 compared to the baseline and recovered toward baseline on day 28. GLS and EF did not show significant differences between Low- and High-CRS groups throughout the follow-up. The Kaplan-Meier analysis demonstrated that there was no significant difference in long-term survival prognosis according to the severity of CRS. Conclusion: This study revealed that CAR-T therapy induced transient changes in NT-proBNP level and GLS especially in High-CRS group in the first 2 weeks, but they did not predict the long-term prognosis.

211P Chemotherapy delivery time affects anti-lymphoma treatment outcome in a sex-dependent manner

Chronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Although chronochemotherapy has been proven to be effective in solid tumors, its value in hematologic malignancy remains unknown. In this study, we tried to identify a chronotherapeutic effect and underlying mechanism of immunochemotherapy in diffuse large B cell lymphoma (DLBCL) patients.

Clinical implications of circulating tumor DNA in predicting the outcome of diffuse large B cell lymphoma patients receiving first-line therapy

BackgroundCirculating tumor DNA (ctDNA) has been proven to be a promising tumor-specific biomarker in solid tumors, but its clinical utility in risk stratification and early prediction of relapse for diffuse large B cell lymphoma (DLBCL) has not been well explored.MethodsHere, using a lymphoma-specific sequencing panel, we assessed the prognostic and predictive utilities of ctDNA measurements before, during, and after first-line therapy in 73 Chinese DLBCL patients.ResultsThe pretreatment ctDNA level serving as an independent prognostic factor for both progression-free survival (PFS, adjusted HR 2.47; p = 0.004) and overall survival (OS, adjusted HR 2.49; p = 0.011) was confirmed in our cohort. Furthermore, the patients classified as molecular responders who presented a larger decrease in ctDNA levels after the initial two treatment cycles had more favorable PFS (unreached vs. 6.25 months; HR 5.348; p = 0.0015) and OS (unreached vs. 25.87; HR 4.0; p = 0.028) than non-responders. In addition, interim ctDNA clearance may be an alternative noninvasive method of positron emission tomography and computed tomography (PET-CT) for predicting better PFS (HR 3.65; p = 0.0033) and OS (HR 3.536; p = 0.016). We also demonstrated that posttreatment ctDNA was a sensitive indicator for detecting minimal residual disease (MRD) in patients with a high risk of recurrence (HR 6.471; p = 0.014), who were otherwise claimed to achieve radiographic CR (complete remission).ConclusionsCtDNA is a promising noninvasive tool for prognosis prediction, response assessment, and early relapse prediction of first-line treatment in DLBCL patients.

Autologous stem cell transplantation in tandem with Anti-CD30 CAR T-cell infusion in relapsed/refractory CD30+ lymphoma

BackgroundLong-term outcome is unfavourable for relapsed/refractory (r/r) lymphoma patients who are resistant to salvage chemotherapy, even after subsequent autologous stem-cell transplantation (ASCT). Although anti-CD30 chimeric antigen receptor (CAR30) T-cell therapy induces high response rates in these patients, the duration of response is relatively limited.MethodsThis open-label, single-center and single-arm pilot study investigated the safety and efficacy of ASCT in tandem with CAR30 T-cell infusion in r/r CD30+ lymphoma. The primary endpoint was safety and key secondary endpoint was overall response rate, overall survival, progression-free survival, and duration of response.ResultsFive classical Hodgkin lymphoma (cHL) patients and 1 anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) patient were enrolled. The median age was 24 years. No patient had prior ASCT. Three patients (50.0%) relapsed for ≥ 2 times and 3 patients (50.0%) had primary refractory diseases. All had a Deauville score of 4 or 5, and 5 patients (83.3%) had a stable or progressive disease (SD/PD) at enrollment. All patients received myeloablative chemotherapy and infused CD34-positive hematopoietic stem cells (HSCs) and CAR30 T cells in tandem, with a median dose of 3.9 × 106/kg and 7.6 × 106/kg, respectively. Five paitents presented with cytokine release syndrome (CRS), all of which were grade 1. No neurotoxicity was observed. All patients had successful HSCs engraftment and reached an objective response, including 5 (4 cHL and 1 ALCL, 83.3%) with a complete response (CR) and 1 with a partial response (PR). With a median follow-up of 20.4 (range, 12.1–34.4) months, all remained alive and maintained their responses.ConclusionOur work demonstrates the combined administration of ASCT and CAR30 T-cell therapy is well-tolerate and highly effective in r/r cHL and ALCL, even in PET-positive or chemorefractory patients who are expected to have inferior outcome after ASCT, although further large-scaled validation in prospective clinical trial is warranted.Trial registration The trial was registered with the Chinese Clinical Trial Registry (ChiCTR, number ChiCTR2100053662).

Evaluation of Haematological Parameters and Lymphocyte Monocyte Ratio as a Prognostic Marker in Diffuse Large B-cell Lymphoma and T Cell Lymphoma Patients- An Observational Study

Background: The present study is a retrospective observational analysis of patients diagnosed with DLBCL and T cell lymphoma during the period of January 2011 to December 2015 at Malabar Cancer Centre, Thalassery. Several studies have shown that ALC and LMR can be used as prognostic indicators for diagnosis, treatment and survival in DLBCL. But there were very few studies done on the correlation of these parameters with T cell lymphoma. So we analysed the influence of haematological parameters in both DLBCL and T cell lymphomas. The primary objective of the present study was to correlate haematological parameters and LMR as predictors of DLBCL and T cell lymphomas. Methods: We analysed total cases of 108 with DLBCL and 25 with T cell lymphomas. The study was done to determine the changes in haematological parameters including WBC count, Platelet count, Hb, HCT, lymphocyte count, monocyte count, ALC, AMC and lymphocyte monocyte ratio in diffuse large B cell lymphoma and T cell lymphomas before and after chemotherapy. Results: The results showed a significant decrease (p˂ 0.05) in the blood platelet counts after chemotherapy in DLBCL. AMC in female patients with DLBCL were decreased (0.69 ± 0.36 to 0.53 ± 0.31; p-value = 0.023) and this was highly significant. LMR was also increased (3.47 ± 3.05 to 5.22 ± 4.34; p-value = 0.048) in female patients with DLBCL. Conclusion: Haematological parameters can be used as a prognostic marker in predicting the extent of disease progression and the effectiveness of the treatment adopted.

Is There Still a Role for Transplant for Patients with Mantle Cell Lymphoma (MCL) in the Era of CAR-T Cell Therapy?

Opinion statementFor years, upfront autologous hematopoietic cell transplant (auto-HCT) has been the standard of care for younger and physically fit mantle cell lymphoma (MCL) patients after chemoimmunotherapy (CIT) induction. Bruton’s tyrosine kinase (BTK) inhibitors have proven to be excellent salvage therapies, but their durability remains a question, especially in high-risk (HR) MCL. Allogeneic HCT (allo-HCT) was the only option for long-term remission and possibly cure for MCL relapse after auto-HCT and sometime as upfront consolidation for a young patient with HR MCL (debatable). We have seen a paradigm shift since the FDA approval in July 2020 of the brexucabtagene autoleucel chimeric antigen receptor T (CAR-T) cell therapy for relapsed and refractory (R/R) MCL with an preliminary evidence suggesting CAR-T may overcome known biological risk factors in MCL. Given its safety profile and excellent efficacy, the role of CAR-T among other approved therapies and HCT may need to be better defined. Based on the current evidence, auto-HCT remains a standard frontline consolidation therapy. CAR-T therapy is a preferred option for patients with relapsed/refractory (R/R) MCL, particularly those who failed BTK inhibitors. In certain high-risk MCL patients (such as high ki 67, TP53 alterations, complex karyotype, blastoid morphology, early relapse after initial diagnosis), CAR-T cell therapy may be considered before BTK inhibitors (preferably on a clinical trial). The role of allo-HCT is unclear in the CAR-T era, but remains a viable option for eligible patients who have no access or who have failed CAR-T therapy. Our review discusses current standards and the shifting paradigms in the indications for HCT and the role of CAR-T cell therapy for MCL. Prospective studies tailored based on risk factors are needed to better define the optimal sequences of HCT and cellular therapy and other approved novel therapies.

ScRNA-sequencing uncovers metabolism and CD52 as new targets in ibrutinib-surviving mantle cell lymphoma cells

Ibrutinib improves the treatment of relapsed or refractory mantle cell lymphoma, amature Bcell neoplasm. However, relapses following treatment with this Bruton tyrosine kinase inhibitor occur frequently, and the outcome of affected patients is poor. Single-cell RNA sequencing (scRNA-seq) can track trends in gene expression of mantle cell lymphoma cells across ibrutinib treatment and new therapeutic targets can be defined based on the detected resistance mechanisms. The ibrutinib-sensitive mantle cell lymphoma cell line REC‑1 was treated with ibrutinib for6 h and48 h. Droplet-based scRNA-seq was performed to examine the transcriptomic alterations of surviving cells using the 10×Genomics platform. Extracellular flux analysis and flow cytometry were applied to further study the observed adaptations to ibrutinib treatment. REC‑1 harbored asubpopulation with potential for crosstalk with microenvironment and therefore greater risk for aggressiveness and drug resistance. Following ibrutinib treatment, NF-κB signaling was turned off. In contrast, the cells upregulated B-cell receptor genes and surface antigens such as CD52, and switched their metabolism to increased dependence on oxidative phosphorylation. Targeting oxidative phosphorylation or CD52 in combination with or as follow-up to ibrutinib might overcome resistance and provide improved prognosis for mantle cell lymphoma patients.

Treatment of Mantle Cell Lymphoma in Transplant Non-Eligible Patients

MCL is a rare but usually aggressive non-Hodgkin lymphoma that most commonly affects the elder population. It is now recognized as a heterogeneous disease with variable biologic and clinical behavior. MCL is considered incurable with current therapies and has historically been associated with a poor prognosis. . Large gains were made in the first decade of the new century when clinical trials established the importance of high-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients and the benefits of maintenance rituximab and bendamustine in older patients. Patients with mantle cell lymphoma (MCL) usually respond to initial combination chemotherapy, but the disease inevitably relapses and often follows an aggressive course. Treatment paradigms have evolved along two lines. Younger, fit mantle cell lymphoma (MCL) patients are generally treated with intensive strategies and older less fit patients with non-intensive strategies. Management of patients with newly diagnosed mantle cell lymphoma (MCL) depends on the age and fitness of the patient. For younger patients, the commonly accepted standard of care is a high-dose cytarabine-based induction chemotherapy followed by autologous stem cell transplantation (ASCT). In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT, the standard-of-care has generally been R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by rituximab, maintenance. In recent years, bendamustine-based therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients. Traditionally, the treatment of MCL has been determined by patients being deemed “transplant-eligible” or “transplant-ineligible”. In particular, greater depth of understanding of the molecular pathophysiology of MCL has resulted in an explosion of specifically targeted new efficacious agents. In particular, agents recently approved by the Food and Drug Administration include the proteasome inhibitor bortezomib, immunomodulator lenalidomide, and Bruton's tyrosine kinase inhibitor ibrutinib. Newer data suggest more tolerable front-line therapy, including regimens incorporating novel agents, may produce similar outcomes to intensive historical induction regimens. This may in turn preclude fewer patients from autologous stem cell transplant and produce better long-term outcomes in transplant-ineligible patients. In the relapsed/refractory setting, novel agents and combination regimens are improving outcomes and changing the landscape of treatment. New therapies with distinct mechanisms of action, including novel immunotherapeutics, antibody-drug conjugates, and non-covalent BTK inhibitors, have demonstrated great potential for improving outcomes post–BTK inhibitor failure in relapsed/refractory mantle cell lymphoma. Although cBTK inhibitor has transformed the treatment landscape in B-cell malignancies, the majority of patients will eventually experience disease progression or treatment intolerance. There are 2 oral BTK inhibitors approved for use in relapsed MCL: ibrutinib and acalabrutinib. Acalabrutinib, originally referred to as ACP-196, is a novel, irreversible BTK inhibitor that was designed to be more kinase-selective than ibrutinib. Orelabrutinib is an orally administered, potent, irreversible and highly selective BTK-inhibitor being developed the treatment of B cell malignancies and autoimmune diseases. Tirabrutinib irreversibly and covalently binds to BTK in B cells and inhibits aberrant B cell receptor signalling in B cell-related cancers and autoimmune diseases. Zanubrutinib received accelerated approval in the USA on 14 November 2019 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, based on overall response rate (ORR) seen in phase II and I/II clinical trials. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. Zilovertamab vedotin is an antibodydrug conjugate, which binds specifically to receptor tyrosine kinase-like orphan receptor-1 (ROR-1), an oncoprotein that is pathologically expressed in mantle cell lymphoma and other malignancies. The development of anti-CD19 CAR T-cell therapy represents a major advance in the treatment of patients with chemorefractory B-cell malignancies.

ABCL-044 Clinical Outcomes of Commercial CD19-Targeted CAR T-Cell Therapy in Patients With Secondary Central Nervous System Lymphoma

We hypothesized that CD19-targeted chimeric antigen receptor (CAR) T-cell therapy is safe and feasible among high-grade B cell lymphoma (HGBCL) patients with secondary central nervous system (CNS) lymphoma. To evaluate the safety and efficacy of CD19-targeted CAR T-cell therapy in patients with relapsed/refractory HGBCL with secondary CNS lymphoma involvement. Patients who had active CNS involvement at the time of CAR T-cell therapy were identified retrospectively in a single-institution database of 101 consecutive HGBCL patients who received either tisagenlecleucel (tisa-cel) or axicabtagene ciloleucel (axi-cel) between 2017 and 2021. The best overall post-CAR T-cell therapy response was defined as the lowest disease burden measured at any time between post-CAR T-cell therapy and additional salvage therapies. Survival analysis was conducted using the Kaplan-Meier method. Overall, 19 HGBCL patients with active secondary CNS lymphoma (5 parenchymal, 9 leptomeningeal/CSF, 5 parenchymal and leptomeningeal) were identified, with a median age of 59 years (16-79 years) at the time of apheresis. All patients in the cohort received tisa-cel with a pre-conditioning regimen of fludarabine and cyclophosphamide. The median follow-up was 5.2 months (range, 0.8-36.8 months) from the date of CAR T-cell infusion. Ten patients had concurrent systemic involvement at the time of infusion. Seventeen patients received bridging therapy, of whom four received radiation therapy (patients/radiation field: 2/craniospinal, 1/whole brain, 1/skull base). Cytokine release syndrome occurred in 16 patients, among whom no grade 3 or higher event was reported. Neurotoxicity syndrome occurred in 9 patients, one of whom reported a grade 4 event. The best objective CNS response (complete response and partial response) rate post-CAR T infusion as per MRI was 58% (n=11): parenchymal (n=3, 60%), leptomeningeal/CSF (n=5, 56%), parenchymal and leptomeningeal (n=3, 60%). The median overall survival and progression-free survival from the start of CAR T-cell therapy were 12.7 months (95% CI: 5.4 months-not reached) and 3.9 months (95% CI: 0.93 months-not reached), respectively. Our data demonstrate that CD19-targeted CAR T-cell therapy is safe and feasible among HGBCL patients with secondary CNS lymphoma. Prospective cohort studies are required for validation.

RITUXIMAB INDUCED LUNG DISEASE IN A MANTLE CELL LYMPHOMA PATIENT RECEIVING MAINTENANCE: CASE PRESENTATION

Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough but no clear evidence of infection. We describe the clinical presentation, management, and response to rechallenge in one mantle cell lymphoma patient who developed R-ILD during maintenance rituximab. Case report 66 years old male with history of mantle cell lymphoma (MCL), who had been treated with RCHOP and underwent autologous stem cell transplantation (ASCT), was diagnosed with relapse 5 years after ASCT. Six courses of rituximab-bendamustine resulted in 2nd complete response and 2-monthly rituximab maintenance was initiated.10 days after 3rd rituximab , he presented with a 1 week history of progressive exertional dyspnea and cough. He was tachypneic and hypoxemic. Thorax HRCT showed peripheral bilateral patchy ground glass opacities and nodular opacities. Bronchoalveolar lavage identified no bacterial,viral or fungal pathogen. With presumptive diagnosis of late R-ILD, methylprednisolone(MP) 1 mg/kg/day was started. In absence of rapidly progressing respiratory failure and fever, the patient was evaulated as non severe R-ILD. Thus, rechallenge with rituximab is being considered due to the risk of relapse of MCL. Discussion: Reported rate of possible R-ILD is <0.03% in over 540,000 patients. Pulmonary complications of rituximab are hypersensitivity pneumonitis, ARDS, interstitial pneumonitis, organizing pneumonia, pulmonary fibrosis, and alveolar haemorrhage. Symptoms of R-ILD are dyspnea, fever, and hypoxemia and HRCT findings include focal alveolar densities, ground glass opacities and alveolar opacification. Time to symptom onset ranges from 1 day to several weeks after 1st infusion with mean mean duration of 3 months. Our patient had received rituximab prior to relapse and developed R-ILD after 9 doses of rituximab for relapse, which is a rare finding. All other causes of potential lung injury had to be meticulously excluded. ILD is a rare but potentially fatal pulmonary toxicity due to rituximab. As the symptoms at presentation are nonspecific, physicians must maintain a high index of suspicion to recognize it early and initiate treatment to avoid severe morbidity and mortality.

CT-321 Uncommon Viral Infections in Patients Treated With CAR-T Cell Therapy: Concurrent Adenovirus and BK Virus Infection in a Mantle Cell Lymphoma Patient Within 30 Days After Receiving Brexucabtagene Autoleucel

Chimeric antigen receptor-T (CAR-T) cell therapy has emerged as an immunotherapy option for several hematological malignancies. Patients treated with CAR-T cell therapy are immunocompromised and prone to infections. However, limited data exist regarding prophylaxis and management strategies, which vary among institutions. We report a single-institution experience of adenovirus (AdV) infection treatment following CAR-T cell therapy. Case report. Academic referral center. A 67-year-old man with high-risk mantle cell lymphoma previously treated with chemoimmunotherapy and ibrutinib received brexucabtagene autoleucel for refractory disease. Treatment was complicated by grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS), warranting corticosteroid treatment that was tapered over 4 weeks, and cytokine release syndrome (CRS), resolved with tocilizumab. The patient was admitted within 30 days post-CAR-T cell therapy with pancytopenia and bilateral pulmonary infiltrates. His only symptoms were fatigue and malaise. A respiratory viral panel was positive for AdV. Further infectious testing revealed AdV viremia at 128,000 copies/mL and viruria at 7.10E+07 copies/mL, as well as BK viremia at 5,200 copies/mL and viruria >62,800,000 copies/mL. The patient was initially treated with intravenous immune globulin and then started on intravenous cidofovir 1 mg/kg with pre- and post-hydration. Adenovirus and BK virus levels were monitored in blood and urine weekly. Cidofovir was continued until the plasma level of AdV was <400 copies/mL on two separate occasions. AdV viremia and viruria, BK virus viremia and viruria, symptoms. Viral levels of AdV steadily decreased over 3 weeks to <190 copies/mL in plasma and 5200 copies/mL in urine. No new symptoms other than intermittent hematuria were noted. BK virus plasma levels increased temporarily, but fluoroquinolones were not given due to allergy and scarce evidence of their efficacy. Immunosuppression in patients receiving CAR-T cell therapy is multifactorial. CRS and ICANS are common acute toxicities that frequently require treatment with immunosuppressive agents. Prolonged use of corticosteroids has been identified as a predictor of infection after CAR-T cell therapy. Clinical trials addressing appropriate infection prophylaxis and treatment in this population are needed.