Cytokine Release Syndrome Grade Research Articles

Effectiveness and safety of CD22 and CD19 dual-targeting chimeric antigen receptor T-cell therapy in patients with relapsed or refractory B-cell malignancies: A meta-analysis.

The efficacy of CD22 or CD19 chimeric antigen receptor T (CAR-T) cells in the management of acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR-T-cell persistence are the leading causes of progressive disease following single-antigen targeting, we evaluated CD22/CD19 dual-targeting CAR-T-cell therapy efficacy and safety in relapsed/refractory B-cell malignancies. The Web of Science, PubMed, Cochrane, and Embase databases were searched until July 2022. Patients confirmed with any relapsed/refractory B-cell hematological malignancies were included regardless of age, gender, or ethnicity, receiving CD22 and CD19-dual-targeting CAR-T-cell therapy. The studies conducted on patients with coexisting other cancer were excluded. We used random-effect models to explore the outcome, and heterogeneity was investigated by subgroup analysis. Fourteen studies (405 patients) were included. The pooled overall response (OR) and complete remission (CR) were 97% and 93%, respectively, for ALL patients. The 1-year proportions of overall survival (OS) and progression-free survival (PFS) were 70% and 49%, respectively. For NHL, OR occurred in 85% of patients, and 57% experienced CR. The results illustrated that the 1-year OS and 1-year PFS were 77% and 65%, respectively. The subgroup analysis showed that the dual-targeting modality achieved higher CR in the following cases: coadministration of CD22/CD19-CAR-T cells and third-generation CAR-T cells combined with ASCT and BEAM pretreatment. The ALL and NHL groups seemed similar in treatment-related toxicity: all grade cytokine release syndrome (CRS), severe CRS, and neurotoxicity occurred in 86%, 7%, and 12% of patients, respectively. Our meta-analysis demonstrated that the CD22/CD19 dual-targeting CAR-T-cell strategy has high efficiency with tolerable adverse effects in B-cell malignancies.

Significance of alkaline Phosphatase After Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma

BackgroundThe inexpensive and readily available biomarkers for cytokine release syndrome (CRS) grading and prognosis assessment in chimeric antigen receptor (CAR)-T therapy are currently lacking. This study examined the significance of alkaline phosphatase (ALP) after CAR-T therapy in patients with relapsed/refractory multiple myeloma (MM). MethodsThis cohort study included 27 patients with relapsed/refractory MM who were treated with CAR-T cells between December 2017 and October 2021. Patients were classified into 2 groups: normal ALP group (peak ALP <125 U/L, n = 10) and high ALP group (peak ALP ≥125 U/L, n = 17). ResultsWithin 1 month of CAR-T cell infusion, the incidence of ALP increases was 63%. We found that ALP levels began to rise in the second week, peaked in the third and fourth weeks, and began to decline in the second month. Moreover, the ALP levels in previous chemotherapy-responsive period were significantly lower than those after CAR-T therapy. Statistical analysis found that patients with increased ALP exhibited higher alanine aminotransferase and aspartate aminotransferase levels, higher and longer CAR-T cell proliferation, more serious CRS, higher cytokine and ferritin levels, and higher initial response rates. In addition, the duration of ALP increase was parallel to the duration of CAR-T expansion. Multivariable Cox‐regression analysis showed that peak ALP was the independent predictor for progression‐free survival (PFS) (HR = 0.029, 95% CI: 0.002-0.369). ConclusionsOur results suggest that the ALP levels after CAR-T therapy could serve as a suitable biomarker for monitoring CAR-T cell proliferation, CRS grading, and prognosis in patients with MM.

A distinct cytokine network distinguishes chimeric antigen receptor T cell (CAR-T)–associated hemophagocytic lymphohistiocytosis-like toxicity (carHLH) from severe cytokine release syndrome following CAR-T therapy

Background aimsWith the increasing application of chimeric antigen receptor (CAR)-T cell therapy in various malignancies, an extra toxicity profile has been revealed, including a severe complication resembling hemophagocytic lymphohistiocytosis (HLH), which is usually disguised by severe cytokine release syndrome (CRS). MethodsIn a clinical trial in whom 99 patients received B-cell maturation antigen CAR-T cells, we identified 20 (20.20%) cases of CAR-T cell–associated HLH (carHLH), most of whom possessed a background of severe CRS (grade ≥3). The overlapping features of carHLH and severe CRS attracted us to further explore the differences between them. ResultsWe showed that carHLH can be distinguished by extreme elevation of interferon-γ, granzyme B, interleukin-1RA and interleukin-10, which can be informative in developing prevention and management strategies of this toxicity. Moreover, we developed a predictive model of carHLH with a mean area under the curve of 0.81 ± 0.07, incorporating serum lactate dehydrogenase at day 6 post-CRS and serum fibrinogen at day 3 post-CRS. ConclusionsThe incidence of carHLH in CAR-T recipients might be relatively higher than we previously thought. relatively higher than we previously. A cytokine network distinguished from CRS is responsible for carHLH. And corresponding cytokine-directed therapies, especially targeting IL-10, are worth trying.

Blinatumomab as salvage therapy in patients with relapsed/refractory B-ALL who have failed/progressed after anti-CD19-CAR T therapy

Background Anti-CD19 chimeric antigen receptors (CARs) T-cell therapy has been shown to have excellent efficacy in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL). But many patients are refractory to anti-CD19-CAR T-cell therapy or relapse again. Methods Five patients with R/R B-ALL did not respond to anti-CD19-CAR T-cell therapy or had a disease progression again after CAR-T cell therapy. They received a salvage therapy of Blinatumomab. The clinical response, CD19 expression on ALL cells, the proportion of CD3+ T cells, level of cytokine levels of interleukin-6 (IL-6), hematological toxicity, grade of cytokine release syndrome (CRS), and immune effector cell-associated neurotoxic syndrome (ICANS) were observed in salvage therapy of Blinatumomab. Results Four patients obtained CR/CRi, even in patients without high expression of CD19 in B-ALL cells, while the other patient received NR after Blinatumomab therapy. The CD19 expression on ALL cells, the proportion of CD3+ T cells, and CD3+CD8+ T cells were deficient in Pt 5, who obtained PR in Blinatumomab therapy. One patient (Pt 3) was diagnosed with grade 0 hematological toxicity. The other four patients were diagnosed with grades 2–3 of hematological toxicity. The CRS was grade 0/one patient, grade 1/three, and grade 2/one. The ICANS was grade 0/four patients, grade 1/one. Rhizopus microsporus pneumonia and cryptococcal encephalopathy in two patients were controlled during Blinatumomab therapy. Conclusions Blinatumomab could be an effective and safe salvage therapy in patients with R/R B-ALL who failed/progressed after anti-CD19-CAR T therapy, even in R/R B-ALL patients without high expression of CD19 in B-ALL cells, patients with CNS leukemia or co-infection. Key messages Some R/R B-ALL patients did not respond to anti-CD19 CAR T-cell therapy or had a disease progression again. Effective and safe salvage therapy for such patients remains to be explored. Blinatumomab could be an effective and safe salvage therapy in patients with R/R B-ALL who failed/progressed after anti-CD19-CAR T therapy, even in patients without high expression of CD19 in B-ALL cells. Blinatumomab could be an effective and safe salvage therapy in patients with R/R B-ALL who failed/progressed after anti-CD19-CAR T therapy, even in patients with CNS leukemia or co-infection.

Risk of infections associated with the use of bispecific antibodies in multiple myeloma: a pooled analysis.

The use of bispecific antibodies (BsAbs) in the treatment of relapsed/refractory multiple myeloma (MM) is showing early promising overall response rates in heavily pretreated patients. Infectious complications related to the use of BsAbs are not well described. We conducted a pooled analysis that included all single-agent BsAbs used in MM with no prior use of different BsAbs. A total of 1185 patients with MM were treated with a BsAb in the studied period (71.6% of the patients treated with an agent targeting B-cell maturation antigen (BCMA). Pooled median follow-up was short at 6.1months (7.5 vs 5.2months for BCMA vs non-BCMA BsAbs, respectively). Adverse events of interest included all grade neutropenia in 38.6%, all grade infections in 50% (n= 542/1083), all grade cytokine release syndrome in 59.6% (n= 706/1185), grade III/IV neutropenia in 34.8% (n= 372/1068), grade III/IV infections in 24.5% (n= 272/1110), grade III/IV pneumonia in 10% (n= 52.4/506), and grade III/IV coronavirus disease 2019 in 11.4% (n= 45.4/395) of the patients. Non-BCMA-targeted BsAbs were associated with lower grade III/IV neutropenia (25.3% vs 39.2%) and lower grade III/IV infections (11.9% vs 30%) when compared with BCMA-targeted BsAbs. Hypogammaglobulinemia was reported in 4 studies, with a prevalence of 75.3% (n= 256/340) of the patients, with IV immunoglobulin used in 48% (n= 123/256) of them. Death was reported in 110 patients, of which 28 (25.5%) were reported to be secondary to infections. Certain precautions should be used when using BsAbs to mitigate the risk and/or identify and treat infections promptly.

Efficacy and Toxicity of CD19 Chimeric Antigen Receptor T Cell Therapy for Lymphoma in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis

The safety and efficacy of chimeric antigen receptor (CAR) T cell therapy in solid organ transplant recipients is poorly understood, given the paucity of available data in this patient population. There is a theoretical risk of compromising transplanted organ function with CAR T cell therapy; conversely, organ transplantation-related immunosuppression can alter the function of CAR T cells. Given the prevalence of post-transplantation lymphoproliferative disease, which often can be difficult to treat with conventional chemoimmunotherapy, understanding the risks and benefits of delivering lymphoma-directed CAR T cell therapy in solid organ transplant recipients is of utmost importance. We sought to determine the efficacy of CAR T cell therapy in solid organ transplant recipients as well as the associated adverse effects, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and compromised solid organ transplant function. We conducted a systematic review and meta-analysis of adult recipients of solid organ transplant who received CAR T cell therapy for non-Hodgkin lymphoma. Primary outcomes included efficacy, defined as overall response (OR), complete response (CR), progression-free survival, and overall survival, as well as rates of CRS and ICANS. Secondary outcomes included rates of transplanted organ loss, compromised organ function, and alterations to immunosuppressant regimens. After a systematic literature review and 2-reviewer screening process, we identified 10 studies suitable for descriptive analysis and 4 studies suitable for meta-analysis. Among all patients, 69% (24 of 35) achieved a response to CAR T cell therapy, and 52% (18 of 35) achieved a CR. CRS of any grade occurred in 83% (29 of 35), and CRS grade ≥3 occurred in 9% (3 of 35). Sixty percent of the patients (21 of 35) developed ICANS, and 34% (12 of 35) developed ICANS grade ≥3. The incidence of any grade 5 toxicity among all patients was 11% (4 of 35). Fourteen percent of the patients (5 of 35) experienced loss of the transplanted organ. Immunosuppressant therapy was held in 22 patients but eventually restarted in 68% of them (15 of 22). Among the studies included in the meta-analysis, the pooled OR rate was 70% (95% confidence interval [CI], 29.2% to 100%; I2 = 71%) and the pooled CR rate was 46% (95% CI, 25.4% to 67.8%; I2 = 29%). The rates of any grade CRS and grade ≥3 CRS were 88% (95% CI, 69% to 99%; I2 = 0%) and 5% (95% CI, 0% to 21%; I2 = 0%), respectively. The rates of any grade ICANS and ICANS grade ≥3 were 54% (95% CI, 9% to 96%; I2 = 68%) and 40% (95% CI, 3% to 85%; I2 = 63%), respectively. The efficacy of CAR T cell therapy in solid organ transplant recipients is comparable to that in the general population as reported in prior investigational studies, with an acceptable toxicity profile in terms of CRS, ICANS, and transplanted organ compromise. Further studies are needed to determine long-term effects on organ function, sustained response rates, and best practices peri-CAR T infusion period in this patient population.

Safety and efficacy of Sleeping Beauty TCR-T cells targeting shared KRAS and TP53 mutations expressed by solid tumors in first-in-human phase 1 study.

2547 Background: Solid tumors present driver mutations in KRAS, TP53, and EGFR genes on their surface in the context of human leukocyte antigen (HLA) molecules to T-cell receptors (TCRs) expressed by T cells. Non-viral genetic engineering of patient T cells with the Sleeping Beauty transposon/transposase system can generate driver mutation-reactive TCR-T cells. Methods: This is a first-in-human phase 1/2 study of autologous Sleeping Beauty TCR-T cell therapy for patients with non-small cell lung (NSCLC), colorectal, endometrial, pancreatic, ovarian and bile duct cancer whose tumors contain at least one of the targeted driver mutations in KRAS, TP53, and EGFR. The primary objective of the phase 1 portion is to define the incidence of dose-limiting toxicities (DLTs) and the maximum tolerated dose or recommended phase 2 dose to be explored in disease specific cohorts during phase 2. Dose levels of 0.1-1 x 1010 (DL1), 1-7 x 1010 (DL2) or 7-15 x 1010 (DL3) TCR-T cells are being explored. Any of the six tumor types or 12 TCRs within the library can be used for the Phase 1 portion of the trial. Results: As of February 14, 2023, three patients have been treated with Sleeping Beauty TCR-T cells on this study. The first was a 34 year old female with stage IV mucinous adenocarcinoma NSCLC refractory to chemotherapy and immunotherapy who received DL1 (0.9 x 1010 TCR-T cells) targeting KRASG12D and HLA-A*11:01, second was a 54 year old female with stage IVA chemotherapy resistant colorectal cancer who received DL2 (6.4 x 1010 TCR-T cells) targeting p53R175H and HLA-A*02:01 and the third was a 60 year old male with stage IV pancreatic cancer refractory to chemotherapy who received DL2 (5.8 x 1010 TCR-T cells) targeting KRASG12V and HLA-A*11:01. Overall, a manageable safety profile with no unexpected adverse events, DLTs or immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. Patients 1, 2 and 3 had cytokine release syndrome grades 2, 3 and 1, respectively, that were self-limiting or resolved with standard management and anti-IL-6 antibody in the case of Patient 2. Best overall responses were partial response for Patient 1 with six month progression-free survival, stable disease for Patient 2 and progressive disease for Patient 3. Persistence of TCR-T cells was observed in all patients at last follow-up and out to 6 months in the case of Patient 1. Acceleration to DL3 is under consideration based on a continued manageable safety profile. Conclusions: This is the first-in-human experience administering Sleeping Beauty TCR-T cells. Signs of efficacy, safety and persistence of TCR-T cells was observed. Thus, this treatment has promise for patients with solid tumors expressing shared mutations in driver genes. The trial is actively enrolling new patients and treating at one of the two highest dose levels. Clinical trial information: NCT05194735 .

Early detection of CRS after CAR-T therapy using wearable monitoring devices: Preliminary results in relapsed/refractory multiple myeloma (RRMM).

e13626 Background: Chimeric Antigen Receptor T-cell (CART) therapy is almost universally given inpatient due to risks of cytokine release syndrome (CRS). This burdens patients, increases bed occupancy, infection risk and costs. In an investigator initiated clinical trial (IIT), we evaluated the feasibility of using wearable devices for detecting CRS following autologous CART therapy in RRMM, in addition to standard of care (SoC). Reliable early CRS monitoring may help transition to outpatient CART. Methods: The remote wearable device (Current Health Inc.) was worn by patients (pts) as part of an IRB approved IIT from CART infusion to discharge and compared to SoC nursing vital signs. The wearable collected continuous measures of temperature, pulse, respiratory rate and O2 saturation. Clinical CRS timepoints were compared to Current Health (CH) data by 1) 2 clinician independent marking of points where CRS began in CH data plots (31 events) 2) Timestamp when a threshold of 2 standard deviations above each pt’s mean baseline temperatures was breached (12 initial events). Outcomes were time to detection of CRS v/s SoC. Wearable adherence was the duration pts wore the device over the total monitoring period. Results: To date, 16 pts were screened and 14 enrolled (87.5% uptake). 12 of 14 pts experienced CRS with concurrent CH and nursing data. Max CRS grades were 1 (10 pts), 2 (1 pt) and 3 (1 pt). Median length of monitoring was 13 (9-14) days. Wearable adherence during overall monitoring period was 71 (50-81) %, and 88 (69-89) % during high-risk period. By visual inspection method, the wearable detected temperature changes consistent with CRS at a median of 205 (range 50-479) mins earlier than SoC for all events. There was excellent inter-observer correlation (95% CI) = 0.952 (0.901-0.977). Inspection revealed associated variability in pulse, respiratory rate and O2 saturation across all CRS grades, with higher tachycardia and drop in SpO2 noted in Grade 2 and 3 CRS. By threshold temperature method, the wearable detected CRS at a median of 195 (range 16-924) mins earlier than SoC; false positive rate 16%, false negative 0%. Conclusions: Initial results suggest wearables can reliably monitor for CRS in the immediate post-CAR-T infusion period and may facilitate earlier detection. High uptake and adherence reflect pts’ acceptance of the technology. Clearly identifiable deviations in all vital signs on visual inspection, with quantifiable trajectory changes relative to baseline offer a strong foundation for a future machine learning approach to CRS alerting, leveraging network physiology. Augmenting CRS prediction by data from cytokine variations and expanding monitoring to bispecific therapy are planned. Reliable CRS detection by wearables may support the transition from inpatient to outpatient administration of cellular therapies.

Single center experience of using Anakinra prophylactically at Day 0 to reduce CD19 CART toxicities.

e19503 Background: Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is an effective line of the treatment for relapsed/refractory CD19 B cell cancers, however navigating Cytokine Release Syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity (ICANS) still remains a challenging task. Corticosteroids and Tocilizumab are currently the mainstay treatment for toxicities but Anakinra, an IL-1 receptor antagonist has also been successfully used to treat patients receiving CART who develop CRS/ICANS. In this study we set out to describe the utility of prophylactic use of Anakinra in patients receiving CART. Methods: We conducted a single center retrospective analysis of patients who received Anakinra for CRS and ICANS prophylaxis per institutional protocol. Patient data including demographics, cancer history, CRS &amp; ICANS American Society for Transplantation and Cellular Therapy Grades, toxicity treatment history and outcomes during their hospitalization were extracted from our medical records. Institutional review board approval was obtained for this review. Results: A total of 19 patients {Diffuse Large B Cell Lymphoma = 10, Follicular = 2,Mantle cell = 2 and Acute Lymphoblastic Leukemia (ALL) = 5} were enrolled in our cohort. The median age of the patients at the time of T cell infusion was 63 years (range, 26-75). CD19 CAR products included Axicabtagene ciloleucel (8 pts; 42.1%), Brexucabtagene autoleucel (6 pts; 31.5%) and Tisagenlecleucel (5 pts; 26.3%). CRS of all grades was observed in 13 patients (68.4%) with severe CRS (grade 3-4) observed in 1 patient (5.2%) (grade 4;12 days). Median CRS duration was 3 days (range, 1-18). Median max CRS grade was observed for 2 days (range, 1-12). Median time to CRS was 5 days (range; 1-8). ICANS of all grades was observed in 12 patients (63.1%), with severe ICANS (grade3-4) in 5 patients (26.3%) {1 patient with grade 4 for 12 days; 4 patients with grade 3 for a median of 2 days (range;1-4)}. Median time to ICANS was 6 days (range, 1-11). Tocilizumab and corticosteroids were used in 9 patients (47.3%) and 11 patients (57.8%), respectively. Median starting day of Tocilizumab and steroid was on day 4(range, 1-6) and day4 (range, 1-21) respectively. Median dose of Tocilizumab was 2 (range, 1-3). Median dose of total Dexamethasone and Methylprednisolone use was 125mg (range, 10-276) and 3.92 g (range, 3-7.4) respectively for a median of 6 cumulative days (range, 1-22). Three patients (15.7%) required ICU transfer with a median stay of 5 days (range, 4-16). 1 patient died of Neurotoxicity on Day 27(Mantle cell) and 2 ALL patients died due to progression after discharge on Day61 and 256. Conclusions: We observed that prophylactically starting Anakinra at Day 0 appeared to improve CRS and ICANS toxicities in patients receiving CART. Further prospective investigations with larger population pools would be required to better understand its role in CAR T toxicity suppression.

Systemic VSV-IFNβ-NIS oncolytic virotherapy in patients with relapsed refractory T-cell lymphoma.

7530 Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach currently under study for relapsed refractory (R/R) hematologic malignancies. The engineered Vesicular Stomatitis Virus VSV-IFNβ-NIS used in this study encodes interferon beta (IFNβ) and sodium iodine symporter (NIS). Virally-encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. Herein, we report the updated results of the phase 1 clinical trial NCT03017820 of a one-time administration of systemic VSV-IFNβ-NIS among patients (pts) with R/R multiple myeloma (MM), T cell Lymphoma (TCL) and Acute myeloid Leukemia (AML) with particular focus on the TCL cohort treated at the highest dose level (DL4) without Ruxolitinib. Methods: VSV-IFNβ-NIS was administered as a single IV dose following a classical 3+3 phase I trial, starting at 5e9 TCID50 DL1 through 1.7e11 TCID50 DL4. A dose expansion cohort of 8 additional R/R TCL pts was added at DL4 in view of an initial signal of activity. The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. Secondary objectives were determination of safety profile and preliminary efficacy of VSV-IFNβ-NIS. Adverse events (AEs) are reported based on CTCAE V4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014) criteria. Results: To date, a total of 43 pts received VSV-IFNβ-NIS: MM (N=21), TCL (N=21) and AML (N=1). In the TCL cohort: at DL4 Group A (no Ruxolitinib), 12 pts were registered, but only 11 pts were treated (mycosis fungoides (MF) N=3; ALK- ALCL N=1; PTCL-NOS N=2; AITL N=4; Nodal PTCL, TFH N=2; ages 33-79). These pts received a median of 3 lines of therapy (range: 1-5). No dose limiting toxicities were observed. Grades 3 and higher AEs were hematologic with transient lymphopenia (63.6%), neutropenia (36.4%) being the most common. The non-hematologic AEs observed included unique toxicities such as CRS grades 1-2 (81.8%); the transient transaminitis grade 1-2 (36.4%) and grade 3 (27.3%) along with thrombocytopenia grade 1-2 (63.6%) and grade 3 (18.2%) were a reflection IFNβ toxicity. All the AEs observed were short lived. Responses were seen in pts with PTCL. At DL4, in pts with systemic PTCL (N=9), there were 5 responses including 3 complete responses (CR) with two long-lasting at 24 months, an ongoing 15 month CR, and a 5 month CR, and 2 partial responses (PR) lasting 5 months in one pts and 6 months in the other. Conclusions: These updated results of single agent VSV-IFNβ-NIS which include pts with PTCL treated at the highest dose level and a dose expansion cohort demonstrates not only the safety of VSV-IFNβ-NIS but also a strong efficacy signal in pts with PTCL with impressive durable responses. Two expansion cohorts at DL4 have been added (20 additional PTCL, 10 B-cell lymphoma pts) to obtain additional data on tolerability and efficacy and biomarkers of response in these pts. Clinical trial information: NCT03017820 .

Baseline and early post-infusion biomarkers associated with optimal response to idecabtagene vicleucel (ide-cel) in the KarMMa-3 study of triple-class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM).

8031 Background: Ide-cel, a B-cell maturation antigen (BCMA) chimeric antigen receptor T cell therapy, significantly improved median progression-free survival (mPFS) and overall response rate (ORR) vs standard regimens (SRs) in patients (pts) with TCE RRMM in the KarMMa-3 study (NCT03651128; Rodríguez-Otero et al. NEJM 2023). Previous analyses in KarMMa (Munshi et al. NEJM 2021) of pts with later-line (4L+) TCE RRMM identified low baseline (BL) levels and complete clearance of soluble BCMA (sBCMA, a measure of tumor burden) and early minimal residual disease (MRD) negativity as correlates of durable response to ide-cel. The current analysis explored the association between biomarkers and efficacy or severity of inflammatory adverse events of ide-cel in KarMMa-3. Methods: sBCMA levels were measured in blood samples collected from pts in KarMMa-3 at BL and regular intervals from treatment (tx) initiation until confirmed progression. MRD status was assessed in bone marrow aspirate (clonoSeq; 10-5 sensitivity) at 6 and 12 mo post infusion and reported in all pts, regardless of response. Biomarker analyses were based on pts who received ide-cel or ≥1 dose of SR. Post hoc analyses assessed correlations between biomarkers and efficacy endpoints or cytokine release syndrome (CRS) and investigator-identified neurotoxicity (iiNT); associations of interest were identified using a ranked sum test and nominal P value &lt; 0.05. Results: Lower BL sBCMA levels were associated with higher ORR ( &lt; partial response [PR] vs ≥PR) in both tx arms (ide-cel, P= 0.0223; SR, P= 0.0395), indicating this may be agnostic of the BCMA-directed modality. Lower BL sBCMA was also associated with higher complete response (CR) rate ( &lt; CR vs ≥CR) in the ide-cel arm ( P= 0.0038). Additionally, lower BL sBCMA levels in the ide-cel arm were associated with lower grade (gr) of CRS (gr 0–1 vs 2 vs ≥3; P= 0.0022) and iiNT (gr 0–1 vs ≥2; P= 0.0113); however, overlapping ranges may limit predictive utility. Further analyses will be presented. In the ide-cel arm, landmark mPFS was longer in pts with undetectable versus detectable sBCMA at 2 mo post infusion (16.3 vs 5.2 mo; HR, 0.26) or at 6 mo (16.8 vs 9.6 mo; HR, 0.62). Furthermore, landmark mPFS was also longer in pts with MRD negativity versus pts with positive/indeterminate MRD status at 6 mo (17.2 vs 5.8 mo; HR, 0.288) or at 12 mo (13.8 vs 4.6 mo; HR, 0.121). Conclusions: BL sBCMA levels correlated with response and CRS and iiNT grade in the ide-cel arm of KarMMa-3, potentially reinforcing the importance of management of BL tumor burden for optimal response to ide-cel. Early clearance of sBCMA at 2 mo, sustained clearance of sBCMA at 6 mo, and MRD negativity at 6 or 12 mo, regardless of clinical response, may be useful biomarkers for identifying pts likely to achieve a complete and durable response to ide-cel. Clinical trial information: NCT03651128 .

Rates of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) from Center for International Blood and Marrow Transplant Research (CIBMTR) data on US subjects (SUBJ) with lymphoma following chimeric antigen receptor T cell therapy (CAR-T).

7528 Background: The engineered T-cell products axicabtagene ciloleucel (axi-cel) and brexucabtagene autoleucel (brexu-cel) are FDA approved for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), respectively. This study investigated real-world rates of CRS and ICANS following CAR-T. Methods: This study analyzed CIBMTR data of US SUBJ receiving axi-cel or brexu-cel for any indication from Oct 2020–Dec 2021 with ≥1 follow-up visit. CRS and ICANS were graded per American Society for Transplantation and Cellular Therapy consensus guidelines. Results: 927 SUBJ (median age, 63 y; men, 65%) from 87 centers were analyzed. Most received axi-cel (76%), 83% of whom had DLBCL or transformed follicular lymphoma (tFL); 24% received brexu-cel (MCL). Most SUBJ had Ann Arbor stage III/IV (63%), no active central nervous system disease (84%), and refractory disease at CAR-T infusion (66%). Among all 589 SUBJ with DLBCL/tFL who received axi-cel, 54% achieved complete response, 17% partial response, and 6% stable disease. 89/715 SUBJ with available data received treatment for CRS prevention, mostly tocilizumab alone (80% [71/89]) or in combination (3% [3/89]). Overall, 766 SUBJ (83%) developed CRS (grade ≥3, 64 [8%]; Table). Of the 89 SUBJ who received CRS prevention treatment, 78% developed CRS, with 3% (3/89) having grade ≥3. 77% of SUBJ with CRS received CRS treatment, 97% of whom received tocilizumab (alone or in combination [eg, with corticosteroids]). Most (64%) SUBJ with grade 1 CRS received treatment, 63% of whom received tocilizumab alone. ICANS occurred in 424/876 SUBJ with ICANS data (48%; Table), of whom 205 (48%) had grade ≥3. ICANS treatment was reported and administered to 86% of SUBJ with ICANS, 92% of whom received corticosteroids. Conclusions: CRS and ICANS incidence rates were consistent with previously published literature and highlight potential burdens of CAR-T. In addition, the treatment landscape for CRS is changing; SUBJ with grade 1 CRS often received treatment. These data will inform the design of future studies aimed at preventing and treating CAR-T toxicities. [Table: see text]

Baseline characteristics identifying patients (pts) with multiple myeloma (MM) treated with idecabtagene vicleucel (ide-cel; bb2121) who are at risk for severe/refractory inflammatory adverse events (iAEs).

e20005 Background: iAEs such as cytokine release syndrome (CRS) and neurotoxicity (NT) are common with CAR T cell therapies such as ide-cel; CRS and NT observed with ide-cel are generally low grade and manageable with tocilizumab (toci) and corticosteroids. Identifying iAE risk with sensitivity and specificity is challenging, suggesting multifactorial etiology and limitations evaluating dynamic processes at specific timepoints. Macrophage activation syndrome (MAS; per CTCAE) has a specific molecular profile representing a homogeneous subgroup within CRS, tending to be more severe/refractory to front-line management. Using longitudinal data on post-infusion soluble factors we aimed to develop a candidate post-infusion inflammatory risk score based on MAS molecular signature and determine associations with pt baseline characteristics. Methods: Statistical learning tools were applied to the longitudinal profile of 34 factors measured over 28 d after ide-cel infusion in 291 pts from KarMMa (NCT03361748) and KarMMa-2 (NCT03601078) to extract features describing the profiles. Unsupervised machine learning-based clustering was applied to these features and enrichment for MAS cases within each cluster was assessed. A metric describing membership in a cluster of interest was used as a candidate post-infusion inflammatory risk score for further correlative analyses. Results: Pts with MAS had cytokine profiles consistent with high levels of pro-inflammatory signalling across multiple inflammatory cell types. Cytokine profiles of MAS were qualitatively similar to those of CRS/NT; however, unsupervised clustering showed a distinct group of pts with MAS. A metric of similarity to the MAS-enriched cluster was defined as a candidate post-infusion inflammatory risk score, posited to identify pts more likely to have more severe/refractory iAEs. This inflammatory risk score positively correlated with CRS and NT grades and frequency of toci usage (Kruskal-Wallis test; all P &lt; 0.001). A prototype predictive model based on baseline pt and clinical characteristics strongly correlated with post-infusion inflammatory risk score (Pearson; ρ = 0.88). Low blood counts, higher tumor burden, and elevated levels of inflammatory markers on the day of ide-cel infusion were associated with a higher inflammatory risk score. Conclusions: A molecular profile of severe/refractory iAEs was preliminarily identified in ide-cel treated pts with MM. This profile enabled derivation of a candidate post-infusion inflammatory risk score and a prototype predictive model of this risk score based on pt baseline characteristics was developed. These results may help identify pts at risk for severe/refractory iAEs, who may be potential candidates for closer monitoring or novel interventions, and warrant further study. Clinical trial information: NCT03361748 , NCT03601078 .

Factors Associated with Increased Risk of Major Cardiovascular Events for Patients Undergoing CAR T Therapy

Introduction: Chimeric antigen receptor (CAR)-T cell therapy use has increased exponentially following its approval for multiple indications in non-Hodgkin lymphomas, multiple myeloma, and acute lymphoblastic leukemia. While cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias are well-described and frequently encountered side effects, a significant proportion of patients experience major adverse cardiovascular events (MACE). This study investigates factors associated with increased risk for MACE. Methods: We performed a retrospective analysis of a consecutive cohort of patients treated with CAR-T therapy at our center between 2018 and 2022. Clinical, laboratory, and imaging parameters were collected. MACE were defined as acute myocardial infarction (AMI), stroke or transient ischemic attack, cardiovascular death, unstable angina, life-threatening arrhythmias, and heart failures. Data was analyzed using SPSS v23. Categorical variables were compared using univariate chi-square test. Results: A total of 126 patients were included. Of these, ten patients (12.5%) had a MACE event. Baseline characteristics including age, sex, body mass index, coronary artery calcium, lipid profile, baseline medications, preceding anthracycline or carfilzomib exposure, cancer type, CRS, ICANS, and tocilizumab use are summarized in Table. The median follow-up period was 8.9 months. Patients who experienced MACE versus no MACE had a significantly higher age at CAR-T cell therapy (74.5 years vs. 64.9 years, p = .009), higher peak C-reactive protein (CRP) with a median of 116.7 mg/dL versus 73.85 mg/dL, p = 0.006 respectively. CRS and ICANS grades were associated with MACE events (p = 0.008 and 0.005, respectively). No echocardiographic differences were found. No progression free or overall survival differences were observed in the groups (p = 0.67 and 0.16, respectively). Conclusions: Our results indicate that patients undergoing CAR-T cell therapy who are older and who experience an increased degree of inflammatory response, reflected by peak CRP level, were associated with MACE. These data suggest that inflammatory markers may be clinically relevant predictors of subsequent MACE in CAR-T therapy-treated patients. Prospective inflammation monitoring combined with trials incorporating anti-inflammatory strategies may mitigate the risk of MACE in this patient population. Keywords: Cellular therapies, Diagnostic and Prognostic Biomarkers, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. G. Kaur Consultant or advisory role: SANOFI, BMS, Janssen, Cellectar, Arcellx Y. F. Madanat Consultant or advisory role: BluePrint Medicines, GERON, OncLive, MD Education, Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology and Novartis Honoraria: BluePrint Medicines, GERON, OncLive, MD Education, Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology and Novartis Educational grants: Blueprint Medicines and Morphosys.

Recovery-model: A model for CAR T-cell-related thrombocytopenia in relapsed/refractory multiple myeloma

BackgroundPatients with multiple myeloma (MM) treated with anti-B cell maturation antigen (BCMA) and chimeric antigen receptor (CAR) T-cell therapy tend to show delayed platelet recovery. Patients and methodsThis single-center retrospective observational study included a cohort of patients with MM treated with anti-BCMA CAR-T cells in ChiCTR-OPC-16009113, ChiCTR1800018137, and ChiCTR1900021153. ResultsFifty-eight patients with MM treated with anti-BCMA CAR-T cells were included. Delayed platelet recovery (platelet count not recovering to 50 × 109/L within 28 days) was observed in 36 % of patients. Regression analysis identified several factors that influenced platelet recovery, and accordingly, a Recovery-Model was developed. A high Recovery-Model score indicates a greater risk of delayed platelet recovery after CAR-T cell infusion and reflects the risk of hematologic toxicity. The model's predictive biomarkers included baseline platelet count, baseline hemoglobin level, logarithm of baseline Ferritin level, and cytokine release syndrome grade. Finally, survival analysis showed a significant relationship between overall survival, delayed platelet recovery (p = 0.0457), and a high Recovery-Model score (p = 0.0011). ConclusionsInflammation-related factors and bone marrow reserves are associated with delayed platelet recovery. Therefore, we developed a model to predict the risk of delayed platelet recovery and hematological toxicity in relapsed/refractory patients with MM after anti-BCMA CAR-T cell treatment.

Tocilizumab for Cytokine Release Syndrome Management After Haploidentical Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis

Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplantation (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplantation cyclophosphamide- (PTCy-) based graft-versus-host disease (GvHD) prophylaxis. Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (myeloablative versus reduced-intensity/nonmyeloablative), and CRS grading (1, 2, versus 3-4). Instead of 22 controls, we chose 21 patients because there was only 1 control matched with 1 TOCI treatment patient in 1 stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (hazard ratio [HR]=3.4 or higher) in transplantation outcomes using a 2-sided 0.05 test. The power would be reduced to about 20% to 30% if the difference was moderate (HR=2.0) using the same test. No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR=0.55; 95% confidence interval [CI]=0.28-1.06, P=.08). Median time to platelet engraftment was 34 days (range 20-81) in TOCI and 28 days (range 12-94) in NO-TOCI group (HR=0.56; 95% CI=0.25-1.22, P=.19). Cumulative incidences of day 100 acute GvHD grades II-IV (P=.97) and grades III-IV (P=.47) were similar between the 2 groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% versus 24%; P=.05). Rates of NRM (P=.66), relapse (P=.83), disease-free survival (P=.86), and overall survival (P=.73) were similar at 1 year after HCT between the 2 groups. Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.

Thrombotic Events Are Unusual Toxicities of Chimeric Antigen Receptor T-Cell Therapies.

Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications.

A combination of pre-infusion serum ferritin, CRP and IL-6 predicts outcome in relapsed/refractory multiple myeloma patients treated with CAR-T cells.

Chimeric antigen receptor - T (CAR-T) cell therapy has shown remarkable efficacy in patients with relapsed/refractory multiple myeloma (R/R MM). However, a subset of patients still experienced progression or relapse, and the predictors of prognosis are little known. We analyzed the inflammatory markers before CAR-T cell infusion, to clarify their correlation with survival and toxicity. This study involved 109 R/R MM patients who received CAR-T therapy between June 2017 and July 2021. Inflammatory markers, including ferritin, c-reactive protein (CRP), and interleukin-6 (IL-6) before CAR-T cell infusion were detected and then categorized by quartiles. Adverse events and clinical outcomes were compared between patients with upper quartile of inflammatory markers and patients with lower three quartiles of inflammatory markers. An inflammatory prognostic index (InPI) based on these three inflammatory markers was developed in this study. Patients were divided into 3 groups according to the InPI score, progression-free survival (PFS) and overall survival (OS) were compared among the groups. In addition, we explored the correlation between cytokine release syndrome (CRS) and pre-infusion inflammatory markers. We found that the pre-infusion high ferritin (hazard ratio [HR], 3.382; 95% confidence interval [CI], 1.667 to 6.863; P = .0007), high CRP (HR, 2.043; 95% CI, 1.019 to 4.097; P = .044), and high IL-6 (HR, 3.298; 95% CI, 1.598 to 6.808; P = .0013) were significantly associated with inferior OS. The formula of the InPI score was based on the HR value of these 3 variables. Three risk groups were formed: (good, 0 to 0.5 point; intermediate, 1 to 1.5 points; poor, 2 to 2.5 points). Median OS for patients with good, intermediate, and poor InPI was not reached, 24 months, and 4 months, respectively, and median PFS was 19.1 months, 12.3 months, and 2.9 months, respectively. In the cox proportional hazards model, poor InPI remained an independent prognostic factor for PFS and OS. Pre-infusion ferritin was negatively associated with CAR T-cell expansion normalized to baseline tumor burden. Spearman correlation analysis showed that pre-infusion ferritin and IL-6 levels positively correlated with the grade of CRS (P = .0369 and P = .0117, respectively). The incidence of severe CRS was higher in patients with high IL-6 compared with patients with low IL-6 (26% vs. 9%, P = .0405). Pre-infusion ferritin, CRP and IL-6 were positively correlated with each peak values within the first month after infusion. Our results suggest that patients with elevated inflammation markers before CAR-T cell infusion are more likely to have poor prognosis.

Impact of Preemptive Use of Tocilizumab on Chimeric Antigen Receptor T Cell Outcomes in Non-Hodgkin Lymphoma

Despite the impressive results of chimeric antigen receptor (CAR) T cell treatment for lymphomas, adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections are major issues that can lead to intensive care unit (ICU) admission and death. Current guidelines recommend tocilizumab for treating patients with CRS grade (G) ≥2; however, the optimal timing of intervention has yet to be determined. Our institution adopted the preemptive use of tocilizumab in cases of persistent G1 CRS, defined as fever (≥38 °C) for >24 hours. This preemptive tocilizumab treatment aimed to reduce evolution to severe (G≥3) CRS, ICU admission, or death. We report on 48 prospectively collected consecutive patients with non-Hodgkin lymphoma treated with autologous CD19-targeted CAR T cells. In total, 39 patients (81%) developed CRS. CRS started as G1 in 28 patients, as G2 in patients, and as G3 in 1 patient. Tocilizumab was administered in 34 patients, including 23 patients who received "preemptive" tocilizumab and 11 patients who received tocilizumab for G2 or G3 CRS from the onset of symptoms. CRS resolved without worsening severity in 19 patients out of 23 (83%) who received preemptive tocilizumab; 4 patients (17%) progressed from G1 to G2 for the development of hypotension and quickly responded to the introduction of steroids. No patients treated with a preemptive approach developed G3 or G4 CRS. Ten out of 48 patients (21%) were diagnosed with ICANS, including 5 patients with G3 or G4. Six infectious events occurred. The overall ICU admission rate was 19%. ICANS management was the most relevant reason for ICU admission (7 patients), and no patient required ICU to manage CRS. No deaths from CAR-T toxicity were observed. Our data indicate that preemptive tocilizumab use is feasible and useful in reducing severe CRS and CRS-related ICU admission, with no impact on neurotoxicity or infection rate. Therefore, early use of tocilizumab can be considered, especially for patients at high risk of CRS.

Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.

Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden. Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.