Immune Effector Cell Therapies Research Articles

Humoral Immunity and Antibody Responses against Diphtheria, Tetanus, and Pneumococcus after Immune Effector Cell Therapies: A Prospective Study.

Patients undergoing immune effector cell therapy (IECT) are at high risk for infections. We assessed seropositivity against pneumococcus, tetanus, and diphtheria in patients before and after IECT and the patients' response to vaccination. We enrolled patients who underwent IECT from January 2020 to March 2022. Antibody levels for diphtheria, tetanus, and pneumococcus were measured before IECT, at 1 month, and 3-6 months after. Eligible patients were vaccinated after IECT. In non-seroprotected patients, we discontinued testing. Before IECT, most patients had seroprotective antibody levels against tetanus (68/69, 99%) and diphtheria (65/69, 94%), but fewer did against pneumococcus (24/67, 36%). After IECT, all patients had seroprotective antibody levels for tetanus at 1 month (68/68) and 3-6 months (56/56). For diphtheria, 65/65 patients (100%) had seroprotective antibody levels at 1 month, and 48/53 (91%) did at 3-6 months. For pneumococcus, seroprotective antibody levels were identified in 91% (21/23) of patients at 1 month and 79% (15/19) at 3-6 months following IECT. Fifteen patients received a pneumococcal vaccine after IECT, but none achieved seroprotective response. One patient received the tetanus-diphtheria vaccine and had a seroprotective antibody response. Because some patients experience loss of immunity after IECT, studies evaluating vaccination strategies post-IECT are needed.

Review of CAR T-Cell Therapy in Multiple Myeloma: A Canadian Perspective.

Multiple myeloma (MM) is an incurable plasma cell malignancy. In the context of the current standard of care therapies in Canada, outcomes among patients with relapsed/refractory multiple myeloma (RRMM), particularly those with triple-class (or more) refractory disease remain poor. Immunotherapies have significantly changed the treatment landscape of MM. Since 2021, two BCMA-targeting CAR T-cell therapy products have been approved for RRMM-namely Idecabtagene vicleucel (Ide-cel) (ABECMA®) and Ciltacabtagene autoleucel (Cilta-cel) (CARVYKTI®), both of which are available in the US and Europe. Although they have shown unprecedented efficacy in RRMM, their clinical and logistical limitations must be acknowledged. MM CAR T-cell therapy is likely to be approved in Canada soon. Therefore, it is timely that we review the latest evidence for commercially available CAR T-cell therapy in multiple myeloma, with a focus on its relevance and impact in the Canadian setting. There will be challenges to access and strategies must be in place to ensure equitable care for all Canadians with MM. Alongside haematologists working in the immune effector cell therapy programs, providers in the community will also play a role in the ongoing monitoring and management of long-term side effects including opportunistic infections and late neurotoxicity.

Metformin and cytokine release syndrome after immune effector cell therapy.

e14535 Background: Cytokine release syndrome (CRS) is the most common complication of chimeric antigen receptor T cells (CAR-T) for hematologic malignancies. We hypothesized that patients undergoing CAR-T therapy who are on metformin will experience a lower incidence or severity of CRS than patients not on this medication. Methods: We evaluated all patients treated with CAR-T at Mayo Clinic Rochester between 1/1/2018 and 1/31/2023, and abstracted relevant clinical and laboratory characteristics to determine the incidence and severity of CRS, PFS as well as OS in patients who were, or were not, on metformin before and during CAR-T therapy for Type 2 diabetes mellitus. We used the Chi-Square test, Mann-Whitney test and the Kaplan-Meier method to analyze data. Results: In the 5-year interval under consideration 237 patients received CAR-T, 168 for non-Hodgkin lymphoma (NHL), and 69 for multiple myeloma (MM). 23 patients (15 NHL and 8 MM) were on metformin at the time of CAR-T. 15 patient developed CRS while on metformin and 175 patients not on metformin (p=0.05). Grade 3 or 4 CRS incidence was 4% in both groups (p=0.41). Of the 153 patients with NHL not on metformin, 121 developed any grade of CRS, while 10 of 15 patients on metformin developed CRS (p=0.268). 4 NHL patients developed CRS Grade ≥3 or higher, while 0 of 15 on metformin developed Grade ≥3 CRS (p=0.237). For the MM patients, the incidence of CRS was 49 patients not on metformin and 5 patients on metformin (p<0.001). 3 MM patients developed CRS Grade ≥3 or higher, while 0 of 8 on metformin developed Grade ≥3 CRS (p=0.346). 12 of 15 patients on metformin with NHL achieved CR compared to 92 of 153 patients not on metformin (p=0.1305). 3 of 8 patients with MM on metformin compared to 24 of 61 patients with MM not on metformin achieved CR or better post CAR-T (p=0.92). Tocilizumab was used in 40% of patients on metformin but in 66% of patients not on metformin (p=0.0016). In NHL patients, PFS from CAR-T infusion was not reached (range: 6.3 to NR) for patients on metformin versus 9.9 months (range: 6.3–19.5) in patients not on metformin (p = 0.3332). In the MM patients, progression-free survival (PFS) from CAR-T infusion was 8.4 months (95% CI: 7.9–not reached [NR]) for patients on metformin and 22.6 months (13.7–NR) for those not on metformin (p = 0.07). Median OS for NHL patients on metformin was not reached (9.766–NR) versus 32.6 months (18.6–NR) for patients not on metformin (p = 0.7022). Median OS was 17 months (95% CI: 8.3 to NR) for patients with MM on metformin vs NR (95% CI: 9.4 to NR) for patients not on metformin (p = 0.2559). Conclusions: In this retrospective study, the co-administration of metformin during CAR-T cell therapy for NHL and MM appears to be associated with a numerically reduced incidence of CRS. The effect appears to be particularly marked in patients with multiple myeloma. Metformin therapy did not seem to affect the response to CAR-T therapy in either NHL or MM.

The Glass Wall: Gendered Authorship Disparities in CD 19 and BCMA CAR-T Clinical Trials for Lymphoma and Myeloma

IntroductionExisting literature suggests that women are significantly underrepresented in the field of hematology-oncology. Women make up 35.6% of hematologists and data on females as site investigators for pivotal trials and authors in publications of pivotal trials in hematologic malignancies, specifically in the novel niche of Chimeric antigen receptor T cell (CAR-T), is sparse. MethodsWe examined the proportion of women in pivotal trials, screening a total of 2180 studies from PubMed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. 2180 initially searched records were filtered by date (2017-2023) and clinical trial status, yielding 149 records. Following a manual review, we included 15 studies that led to the approval of or anticipated approval of CD19 and BCMA CAR-T therapies in lymphoid and plasma cell malignancies. We examined overall number of female authors, number of lead female authors, and ratio of all authors to female authors in the 15 trials, which were all high impact, cited on average 1314 times. ResultsOf the 436 authors assessed, 132 were female, correlating to 29.5% female authorship. The only study with female authorship >50% was ELIANA, a 2017 pediatric study. 7 of the 15 studies had female lead authors; notably, 6 out of 7 of these studies were published in 2021 or later. ConclusionIn conclusion, our data suggests gender iniquities for female investigators exist in the field of immune effector cell therapy. We suggest further investigation and strategies to decrease gendered authorship disparities.

Prolonged cytopenias after immune effector cell therapy and lymphodepletion in patients with leukemia, lymphoma and solid tumors

Background aimsThe success of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell malignancies has led to the evaluation of CAR T-cells targeting a variety of other malignancies. Although the efficacy of CAR T-cells is enhanced when administered post-lymphodepleting chemotherapy, this can trigger bone marrow suppression and sustained cytopenia after CD19.CAR T-cell therapy. Additionally, systemic inflammation associated with CAR T-cell activity may contribute to myelosuppression. Cytopenias, such as neutropenia and thrombocytopenia, elevate the risk of severe infections and bleeding, respectively. However, data on the incidence of prolonged cytopenias after immune effector therapy in the solid tumor context remain limited. ObjectiveWe compared the incidence of prolonged cytopenias after immune effector therapy including genetically modified T-cells, virus-specific T-cells (VSTs) and NKT-cells, as well non-gene-modified VSTs for leukemia, lymphoma, and solid tumors (ST) to identify associated risk factors. MethodsA retrospective analysis was conducted of 112 pediatric and adult patients with relapsed and/or refractory cancers who received lymphodepleting chemotherapy followed by immune effector therapy. Patients treated with 13 distinct immune effector cell therapies through 11 single-center clinical trials and 2 commercial products over a 6-year period were categorized into 3 types of malignancies: leukemia, lymphoma and ST. We obtained baseline patient characteristics and adverse events data for each participant, and tracked neutrophil and platelet counts following lymphodepletion. ResultsOf 112 patients, 104 (92.9%) experienced cytopenias and 88 (79%) experienced severe cytopenias. Patients with leukemia experienced significantly longer durations of severe neutropenia (median duration of 14 days) compared with patients with lymphoma (7 days) or ST (11 days) (P = 0.002). Patients with leukemia also had a higher incidence of severe thrombocytopenia (74.1%), compared with lymphoma (46%, P = 0.03) and ST (14.3%, P < 0.0001). Prolonged cytopenias were significantly associated with disease type (63% of patients with leukemia, 44% of patients with lymphoma, and 22.9% of patients with ST, P = 0.006), prior hematopoietic stem cell transplant (HSCT) (66.7% with prior HSCT versus 38.3% without prior HSCT, P = 0.039), and development of immune effector cell-associated neurotoxicity syndrome (ICANS) (75% with ICANS versus 38% without ICANS, P = 0.027). There was no significant association between prolonged cytopenias and cytokine release syndrome. ConclusionsImmune effector recipients often experience significant cytopenias due to marrow suppression following lymphodepletion regardless of disease, but prolonged severe cytopenias are significantly less common after treatment of patients with lymphoma and solid tumors.

Metformin and Cytokine Release Syndrome after Immune Effector Cell Therapy

Metformin and Cytokine Release Syndrome after Immune Effector Cell Therapy

Differences in Diagnostic Characteristics and Outcomes in Adults with Malignancy-Associated and Non-Malignancy-Associated Hemophagocytic Lymphohistiocytosis (HLH)

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by life-threatening inflammation. In adults, roughly 50% of HLH manifests in association with an underlying malignancy (most commonly lymphoma), and the remaining cases are due to infection, autoimmune disease, late presentations of genetically-driven HLH, and sometimes multifactorial or idiopathic causes. Although the majority of prospective data for HLH are derived from children, survival outcomes for non-malignant causes of adult HLH (nmHLH) are thought to rival pediatric HLH; however, outcomes for malignancy-associated HLH (mHLH) appear to be substantially worse (~10-30% 5-year overall survival) in the literature. As diagnostic and prognostic models for HLH outcomes have primarily been constructed using pediatric data, attempts have been made to develop diagnostic indices applicable to adult HLH (particularly mHLH). Here, we summarize the clinical and laboratory characteristics of mHLH and nmHLH in a retrospective observational study, and evaluate the role for common diagnostic tools for adult HLH. Methods: Patients &amp;gt;18 years old, fulfilling at least five of the HLH-2004 diagnostic criteria with at least 3 months of follow-up (among survivors) were enrolled. All included patients received definitive HLH therapy, including cancer-directed therapy when appropriate, but those receiving only systemic steroids were excluded. Treatment-related HLH, such as HLH occurring with immune effector cell therapy or hematopoietic cell transplantation, was excluded. Clinical and laboratory parameters reflect the most recent values on or prior to diagnosis and treatment initiation. Differences between mHLH and nmHLH were assessed with two-tailed t-test or Wilcoxon test. Survival outcomes are estimated by Kaplan-Meier. Multivariate analysis was performed using Cox proportional hazards and compared using logrank test. Results: 42 adults were diagnosed with HLH requiring HLH-specific therapy (23 mHLH, 19 nmHLH) between 3/2016 and 3/2023 with a median age of 50 (range 21-75). Of the mHLH cases, 44% were due to T/NK cell lymphomas; 52% were B cell lymphomas including 26% Hodgkin. Of the nmHLH cases, most were due to infection (47%); while others were deemed to be idiopathic (26%) or genetic (16%). All patients with mHLH had fever (v 84% in nmHLH); 91% met cytopenia criteria (v 68%), and absolute neutrophil count (ANC), hemoglobin (Hgb), and platelet count (plt) were all statistically lower than in nmHLH (mean ANC 3.2 v 11.3; Hgb 7.8 v 8.5; plt 43 v 88; p&amp;lt;0.05). Mean soluble interleukin-2 (sIL2) level was significantly higher in mHLH (39,579 pg/mL v 18,484) after adjusting for a single outlier. All other HLH-2004 diagnostic parameters were not statistically different between mHLH and nmHLH, including ferritin and sIL2/ferritin index. All mHLH patients had an underlying lymphoma and met the optimized HLH inflammatory (OHI) index except a single patient with leukemia; 4 patients with nmHLH did not meet the OHI index. In 79% of patients, the HLH94 regimen was incorporated in the induction regimen; the remaining utilized chemotherapy or antibiotics, with and without adjunctive steroids. 4 cases proceeded to allogeneic transplantation. Relapse rates were high, with median relapse-free survival (RFS) being 37 days (23 v 47 days for mHLH and nmHLH, respectively); median overall survival (OS) was 96 days (86 v 149 days). RFS/OS was not statistically different between mHLH and nmHLH. Age was a significant predictor of OS but not RFS; no other diagnostic parameter was predictive, including degree of ferritin or sIL2 elevation. 13 patients were alive at the time of last follow-up (6 mHLH, 7 nmHLH). Conclusions: In this single center retrospective study, both mHLH and nmHLH requiring HLH-directed therapy demonstrated poor survival outcomes in adults. The degree of cytopenias and sIL2 elevation were more significant in mHLH in comparison with nmHLH. The OHI index identified all cases of lymphoma-associated HLH but neither ferritin nor sIL2 levels were predictive of survival. These data emphasize the need for therapeutic advances for management of adults with mHLH and nmHLH and continued optimization of diagnostic criteria for adult HLH.

Heterogeneity in Access and Toxicity Management of Commercially Available BCMA-Directed CAR-T and Bispecific T-Cell Engager Therapy Among the International Myeloma Community

Introduction: BCMA-directed CAR-T and Bispecific T-cell engager (BiTE) therapies have shown remarkable overall response rates in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). This has led to the approval of idecabtagene vicleucel, ciltacabtagene autoleucel and teclistamab by the FDA, EMA and other regulatory agencies. We performed a global survey on accessibility, practice patterns, and toxicity management of commercially available CAR-T and BiTE therapies. Methods: An online survey was completed by clinicians attending the International Myeloma Society's Immune Effector Cell Therapies in Multiple Myeloma Workshop, in-person or virtually, made available for 30 days after the meeting held in March 2023, Boston, MA. Results: 87 clinicians from 16 countries completed the survey, most practicing in an academic practice (86%) and in an urban environment (89%). Sixty-four percent of the respondents practice in North America followed by Europe (25.3%) including Germany, United Kingdom, Ireland, Italy, Netherlands, Spain, France, Greece, and Cyprus, and 6.9% from Asia and 3.4% from Australia. Seventy-seven percent reported CAR-T cell therapy was approved in their country with 44.8% treating 1-5 patients and 14.9% treating &amp;gt;5 patients per month; 67% reported BiTE therapy was approved in their country with 14.9% treating &amp;gt;5 patients per month. Of evaluable responses (n = 40), 62% administered CAR-T therapy inpatient and 15% administered CAR-T therapy outpatient ≥ 50% of the time. Length of time between decision to treat with CAR-T therapy to infusion was 6-12 weeks for 42% of responders and &amp;lt;6 weeks for only 20%. Most (75%) reported inpatient administration of BiTE therapy step-up dosing; 17.5% reported outpatient step-up dosing administered ≥ 50% of the time. Use of institutional or practice SOPs for CAR-T and BiTE therapy patient selection was reported by 85% and 58%, respectively, with the factors influencing SOP outlined in Table 1. Of available CAR-T therapies, 53% prefer cilta-cel and 23% reported CAR-T therapy preference depended most on patients' co-morbidities/frailty (89%), timing of next available apheresis (67%), age (56%), CNS disease (44%) and other factors. Maintenance therapy after CAR-T therapy was reportedly used by 25% and 5% of respondents in 1-10% and 11-50% of their patients, respectively, to “maintain level of response achieved” (50%) or “achieve a deeper level of response” (25%). About half (43%) of the respondents reported using an SOP or particular criteria for secondary Hemophagocytic Lympho-Histiocytosis/Macrophage Activation Syndrome/CAR-related-HLH (sHLH/MAS/CarHLH) management that varied between the use of ASTCT Working Group IEC associated HLH-like syndrome Criteria (47%) (Hines 2023), CARTOX HLH Criteria (24%) (Neelapu 2017) and HLH-2004 criteria (6%). Tocilizumab was used as cytokine release syndrome (CRS) prophylaxis only by one responder. Keppra neurologic prophylaxis was used by 47.5% and 15% of responders for CAR-T and BiTE therapy, respectively. Delayed neurotoxicity with CAR-T was reported in 1-5% of patients by 57.5% of responders and 6-10% of patients by 15% of responders; most common manifestations were other movement/neuromuscular disorder (62%), nerve palsy (55%), and Parkinsonism (45%). Infectious prophylaxis was used to protect against HSV (92.5%), PJP (90%), bacterial pathogens (55%), fungal pathogens (60%), and IVIG (77.5%). However, criteria for infectious prophylaxis use varies widely incorporating IgG levels, infectious history, CD4+ count, B-cell aplasia and cytopenias (48.1 - 88.9%). Most respondents (46.3 - 86.5%) reported completing an infectious work-up including CMV, EBV, Hep B/C, and HIV ( Table 2). Conclusions: Trends of CAR-T and BiTE therapy use and patterns of concurrent prophylactic and supportive care in MM vary widely among academic centers across the globe, demonstrating a need for further understanding of toxicity pathogenesis, toxicity management and consistent guidelines. This survey also demonstrates the great unmet need for access beyond urban centers among the international myeloma community. Prospective studies and claims data analysis should be utilized to evaluate the longitudinal cost of care, quality of life, duration of response and management of infectious disease, neurological or related complications of CAR-T and bispecific TCE therapies.

Prior Immune Effector Cell Therapy, Is Not Associated with an Increased Infectious Risk of Subsequent Bispecific Antibody Therapy for Multiple Myeloma

Introduction: Bispecific antibodies (BisAb) are effective therapies for relapsed myeloma yet associated with high risk of potentially severe infections. A prior study from our center did not associate any baseline characteristics with 90-day risk of infection. In clinical practice patients are already receiving sequential immune effector cell therapy (IET; BisAb or CAR T) it remains unclear whether this compounds the infectious risk. Herein, we examined whether a prior T-cell redirecting therapy predisposes to increased risk of infection during subsequent BisAb. Methods: This is a single-center, retrospective analysis of patients receiving BisAb therapy targeting B-cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D), or Fc receptor-homolog 5 (FCRH5) between January 2017 and February 2023. BisAb treatment was considered a treatment event (TE) such that if a patient received two different BisAbs, this would be considered two separate TEs. We obtained clinical data from before BisAb therapy start date: prior CAR T therapy, prior BisAb therapy, and infections 90 days before TE). Infection data during the full duration of BisAb therapy was also collected from the time of the first priming dose until 30 days after the last BisAb dose. For follow up for infections, we included any TE with at least one target dose of BisAb. We utilized two-sample proportion tests to analyze the differences in rates of infections between the BCMA and non-BCMA groups. Results: 91 patients and 123 TE episodes were identified. The TE episodes consisted of 40 with BCMA-directed therapy, 48 with GPRC5D-directed therapy, and 35 with FcRH5-directed therapy. Of these 123 treatment episodes, 26 TEs had 1 prior CAR T and 2 TEs had 2 prior CAR T and 28 TEs had received 1 prior BisAb and 6 TEs had received 2 prior BisAb. The most common infections were viral (46.1%) followed by bacterial (30.4%) and fungal (5.2%). We evaluated the relationship between prior IET (either CAR T or BisAb therapy) and incidence of infections during and up to 30 days BisAb (Table 1). In TEs with at least 1 prior CAR T the incidence of infections was: 62.5% (BCMA), 44% (GPRC5D) and 64% (FCRH5). For BCMA vs non-BCMA, the incidence of infections was 62.5% vs 55% (p=1.0). In TEs with at least 1 prior BisAb, the incidence of infections following subsequent BisAB was 50% (BCMA), 100% (GPRC5D) and 50% (FCRH5). For BCMA vs non-BCMA, the incidence of infections was 50% vs 65% (p=0.6). In TEs without prior IET, the incidence of infections was 50% (BCMA), 42.8% (GPRC5D), 75% (FCRH5). For BCMA vs non-BCMA, the incidence of infections was 50% VS 52.9% (p=1.0). On comparing these cohorts, we found no significant differences between the BCMA and non-BCMA BisAb therapy for following groups: prior BiSAb, prior CAR T, and the group without prior IET. We evaluated TEs with infections in the 90 days prior to BisAb and their relationship to infections during the first 90 days following BisAb therapy. The infection rate in the 90 days following BisAb therapy increased in TEs with earlier infection in the 90 days before BisAb priming dose from 30% to 43% for BCMA and 34.9% to 45.9% for non-BCMA BisAb. Conclusions: In this retrospective study we found similar rates of infection between groups with and without prior IET exposure. In patients who had infections during the 90 days before BisAb therapy, there was an increase in infection rate from baseline of 13% for BCMA BisAb and 11% from non-BCMA BisAb in the first 90 days after BisAb therapy. This is the largest cohort to report real-world data on infections following BisAb therapy after prior IET.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS): A Review of Pharmacovigilance

Background: CAR-T cell therapies have revolutionized cancer therapeutics with durable responses in hematologic malignancies. However, toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are well-established off-target effects of CAR-T therapy. Immune effector cell (IEC) therapy can result in hemophagocytic lymphohistiocytosis (HLH)-like events, which are now understood as separate entities. Rare and fatal, HLH is characterized by abnormal activation of natural killer (NK) cells, macrophages, and cytotoxic T-lymphocytes; this leads to supraphysiologic production of cytokines and immune-mediated organ system damage. Expert consensus review defines IEC-HS as the development of pathologic features of HLH/macrophage activation independent from CRS and ICANS attributed to IEC therapy, including new onset or worsening cytopenia, hyperferritinemia (&amp;gt;2 times the upper limit of normal), coagulopathy with hypofibrinogenemia, and elevated transaminases. Few clinical studies have shown IEC-HS in Acute Lymphocytic Leukemia (ALL), especially in the pediatric and adolescent populations. However, the incidence and risk of IEC-HS exposure to CD19 and BCMA CAR-T are yet to be determined in B-cell lymphomas and Myelomas. The FDA Adverse Event Reporting System (FAERS) contains circumstantial case reports and serious post-CAR-T therapy IEC-HS. This retrospective analysis from the FAERS aims to address these questions and estimate the risk of IEC-HS with CAR-T cell therapies. Methods: FAERS is a publicly accessible database of adverse event reports associated with various therapies, including CAR-T cell therapies. To estimate the risk of HLH-like syndrome associated with CAR-T treatment, we analyzed the reporting of four CD19 CAR-T therapies (Axicabtagene Ciloleucel, Brexucabtagene Autoleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel) and BCMA CAR-T (Idecabtagene Vicleucel) from the database between 2016 and 2023. Statistical analysis involved a disproportionality analysis using a reported odds ratio (ROR). OpenVigil, a software package used to analyze pharmacovigilance data, enabled the calculation of the ROR with a 95% confidence interval (CI). ROR greater than one, p&amp;lt;0.05, and a confidence interval not including one was considered significant. Results: Between 2016 and April 2023, the FAERS database recorded 8,302 CD19 CAR-T therapies (axicabtagene ciloleucel, n = 4,496; brexucabtagene autoleucel, n = 713; tisagenlecleucel n = 27,51; lisocabtagene maraleucel; n = 342) and 472 BCMA CAR-T therapies, Idecabtagene Vicleucel. We identified 177 reported HLH events as the primary events in patients receiving CAR-T therapies (CD19 CAR-T n = 165; BCMA n = 12). Thirty-six (20.3%) were reported as single IEC-HS, 96 (54.2%) as combined IEC-HS and CRS, 9 (5.1%) as combined IEC-HS and ICANS, and 36 (20.3%) as having all three IEC-related toxicities. The median age was 57 (4-89) years, and males &amp;gt; females at a ratio of 2:1. The study's limitation is that medical personnel reported most of the adverse events (n = 166 of 177 [94%]), and it is unclear if the diagnosis of IEC-HS followed current diagnostic criteria. The CD19 CAR-T was primarily associated with B-cell lymphomas (n = 104, 60.0%), followed by R/R ALL (n= 39, 22.0%) and Chronic Lymphocytic Leukemia, CLL (n = 3, 1.7%). Their combined elevated risk for IEC-HS was greater than that of patients in the database who had not been exposed [ROR, 63.6; 95% CI 54.7-74.1] [p&amp;lt;0.001]. In addition, we conducted a stratified analysis for each drug. Tisagenlecleucel had the highest risk for IEC-HS among the CD19 CAR-T drugs [ROR, 82.3; 95% CI 65.5-104.0] [p&amp;lt;0.001]. The risk was also significant with Idecabtagene Vicleucel [ROR, 73.5; 95% CI 41.4-130.5]. Overall, the results of the study indicate a strong association between CAR-T cell therapy exposure and IEC-HS. Conclusion: CAR-T cell therapy poses a risk for rare IEC-HS, CRS, and ICANS, necessitating early detection to minimize morbidity and mortality. The study's results will be compared to the institutional patient cohort for annual meeting. Understanding factors contributing to this rare complication is crucial for optimizing patient outcomes and ensuring safe CAR T cell therapy use.

Outcomes in Patients with Relapsed Refractory T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Treated with CAR-T Cell Therapies or Salvage Chemotherapy - a Single-Institution Experience

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of large B-cell lymphoma. A substantial subset of THRLBCL patients (pts) relapse after frontline anthracycline-based therapy. There is a scarcity of outcome data on therapy options for relapsed/refractory (r/r)THRLBCL, particularly CD19 CAR-T therapy.A recent genetic and spatial analysis provided critical insights into the complex interactions at the tumor-immune interface in THRLBCL. Understanding the mechanisms by which tumor cells evade the immune system is crucial in designing treatment strategies. This retrospective study aims to analyze clinicopathologic data in pts with r/r THRLBCL with the goal of identifying patterns that may influence response rates and long-term survival. METHODS: Pts who were evaluated and treated at MD Anderson Cancer Center (MDACC) with THRLBCL from 1/2005-5/2023 were included in the analysis. We reviewed demographic, clinical and pathological characteristics, treatments, and outcomes through an approved IRB protocol. We excluded cases with ambiguous diagnosis (such as DLBCL with increased infiltrate of T-cells and/or histiocytes), missing treatment, and/or no follow up information. Progression-free survival (PFS) and overall survival (OS) were calculated from start of treatment until progression or death using Kaplan-Meier. Log-rank test was used to evaluate the difference between pt groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for all analyses. RESULTS: A total of 212 pts were reviewed, and we excluded 86 pts who did not meet selection criteria. Out of 126 pts, 63 with biopsy-confirmed relapse after 1st line chemoimmunotherapy were included in the analysis (Table-1). The median age was 49 (20-79 years); and 49 pts (78%) were males. Twenty-one (34%) pts had documented NLPHL at the time of or predating the THRLBCL diagnosis. At relapse, 93 % had advance stage disease (stage 3 and 4). Splenic involvement was documented in 57% and 80% of pts had one or more sites of extra nodal disease. Most pts who relapsed received front line RCHOP (77%) or R-EPOCH (11%). Twenty-six pts (41%) had primary refractory disease, and 24 pts (38%) relapsed within 12 months. The median time to progression from 1st line treatment was 7.4 months(2.2~145.9 months). The most common 2 nd line therapy was salvage chemotherapy (82%) such as R-ICE (n=41), R-DHAP(n=4), R-GemOx (n=3). Overall response rate (ORR) to 2 nd line salvage chemotherapy was 75% with CR of 57%. For pts who received 2nd line salvage chemotherapy with the intent to undergo HSCT, the PFS at 2 years was 53% (95% CI: 0.4-0.68, p&amp;lt; 0.0001) and OS was 64% (95% CI: 0.5- 0.8, p&amp;lt; 0.372). Among pts who received consolidation with HSCT, (n=30, 57%), 5 pts relapsed at the time of last follow up.With a median follow-up time of 60.1 months (95% CI: 33.6~90.3 months), the median PFS from all 2nd line treatments was 11 months (95% CI: 4.7 ~ NA ) and for pts who received salvage chemotherapy with HSCT intent was 50.26 (95% CI: 7 ~ NA months). The median OS from 2nd line for all pts was 77.3 months (95% CI: 22.2 ~ NA months) and for pts who received salvage chemotherapy with HSCT intent OS was not reached (95% CI: 32 ~ NA months). Among 11 pts who received 3 rd line salvage chemotherapy, the median PFS was 2 months, and only one pt received HSCT. All pts eventually had progressive disease. Eleven pts received CD19 CAR-T (Axi-cel-9, Liso-cel-2),(table-1) 6 pts received as 2 nd line, 4 received as 3rd line and 1 pt received as 4 th line. Best ORR to CAR-T at any lines was 45% with CR of 36.4%. At a median follow-up time of 12.3 months (95% CI: 2.4 ~ NA months), all but one pt had disease progression. Median PFS was 1.7 months (95% CI: 1.1 ~ NA months). 6-month PFS was 21% (Figure 1). One pt who had response experienced prolonged remission of 17 months before relapsing. CONCLUSION: Our study highlights the unique biology and poorer prognosis of TCHRBCL compared to other DLBCL subtypes. Despite the success of CD19 CAR-T therapy in DLBCL, TCHRBCL pts have shown limited response to these therapies, demonstrating the challenges of achieving long-term remission in this group. Our study shows the high unmet need for improved therapies that can target the unique biology in TCHRBCL. We plan to report a comparative spatial analysis evaluating the tumor-immune interface that can contribute to resistance to Immune effector cell therapies at the meeting.

Trends in Access to Cellular Therapies in Multiple Myeloma (TACTUM): Perspectives of Treating Versus Referring Physicians

Introduction: Approved BCMA-directed cellular therapies (BDCT) for multiple myeloma (MM) include chimeric antigen receptor T cell therapies (CART): idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), and T cell engagers (TCE) such as teclistamab (tec). Despite promising efficacy and safety profiles, limited access is a challenge since the first BDCT approval in 2021. We conducted this TACTUM-23 survey to gain insights into the practices and perspectives of oncologists from BDCT-referring and treating centers and identify potential areas of improvement. Methods: The cross-sectional survey was developed with input from BDCT-prescribing oncologists, referring oncologists, and a biostatistician. “ BDCT centers” were centers administering BDCT and included “CART-centers” and TCE-Centers“ where these respective therapies were administered, while others were grouped as ”BDCT-referring centers“ including ”CART/ TCE- referring centers“. Three sections were included: demographics, choice of BDCT in real-world scenarios, and logistical barriers to managing adverse effects at referring centers. The survey was administered electronically from 6/16/23-6/27/23 to a diverse sample of practicing US oncologists from various medical institutions collaborating with USMIRC. Only those who completed 100% of the survey by 7/1/23 were included in the interim analysis. Results: The survey was distributed to 247 oncologists of which 66 (27%) responses were recorded. 37(15%) completed 100% of the survey and were included in this analysis. 73% of oncologists were from academic institutions, and 54% treated plasma cell disorders only. Most oncologists (70%) were from CART-centers. Similarly, most (81%) were from TCE-centers. 11% of centers offered only TCE and not CART while none exclusively offered CART alone. Among CART-centers, 54% offered both approved therapies (ide-cel/cilta-cel). Oncologists practiced in the Midwest (43%), South (22%), West (19%), and Northeast (16%). Choice of BDCT in Real-World Scenarios: TCE was the favored BDCT for patients meeting criteria but with either significant comorbidity, renal failure, poor performance status, mild cognitive impairment, age &amp;gt;75yr, rapidly progressive disease, or post-CART relapse. CART was preferred only for scenarios of extramedullary disease, allogeneic stem cell transplant recipients, and renal failure on dialysis. Respondents ranked choices of potential barriers to access based on their order of importance as below ( Figure 1) Barriers to CART access: Financial burden was the top-ranking barrier (45%) by oncologists from CART-referring centers, while the number of production slots allocated per month was the top barrier (69%) by oncologists from CART-centers. Notably, relocation and caregiver requirements were ranked as top barriers by 27% of oncologists from CART-referring centers but by none of the oncologists from CART-centers. Barriers to TCE access: Among oncologists from TCE-referring centers, the majority (43%) felt that financial burden was the top barrier to access for TCE while most oncologists (63%) from TCE-centers identified hospitalization requirements as the top barrier. Infrastructure for side effect management in BDCT-referring centers: Most oncologists at BDCT-referring centers reported the ability to manage low-grade cytokine release syndrome (CRS), immune effector cell therapy associated neurotoxicity syndrome (ICANS), infections and cytopenia, as shown in Figure 2 Conclusions: While limited by the relatively low number of responses, this survey is the first to specifically delineate barriers to BDCT access by treating versus referring centers in MM. The primary concerns are financial burden, relocation requirements for CART, and hospitalization for TCE. Most oncologists at BDCT-referring centers expressed comfort with identifying and managing low-grade CRS and ICANS, suggesting the readiness of referring oncologists to engage in toxicity management. Future steps to increase collaboration between treating and referring centers include outpatient BDCT programs and clearer guidelines for transferring patients after the initial month of BDCT therapy. Relocation and caregiver requirements, which were perceived as barriers by referring but not treating centers, need to be addressed as well.

The Glass Wall: Gendered Authorship Disparities in in CD 19 and BCMA CAR-T Clinical Trials for Lymphoma and Myeloma

Introduction: Existing literature suggests that women are significantly underrepresented in the field of hematology-oncology. Data from 2021 suggests that women make up 35.6% of hematologists, and thus the disparity continues in clinical trial research authorship. Minorities including women receive fewer awards, deliver fewer board review lectures, and hold fewer professorships, and leadership positions in clinical departments and professional organizations. To further investigate this issue, we conducted a study to assess the gender gap in authorship across 13 pivotal clinical trials that led to the approval of CD19 and BCMA Chimeric antigen receptor T cell (CAR-T) therapies. Methods: We included the 13 pivotal trials that led to the approval of CART for Acute Lymphoblastic leukemia (ALL), lymphoma and myeloma , published between 2017-2022. These included the trials: ELIANA, ZUMA-1, JULIET, ZUMA-2, KarMMa, TRANSCEND, ZUMA-5, CARTITUDE-1, ZUMA-7, ZUMA-3, TRANSFORM, PILOT, and ELARA. We examined the overall number of female authors, the number of lead female authors as defined as first, second, or last author, and the ratio of all authors to female authors. 367 total authors were included in the analysis, with several authors being included more than once for their work on separate studies. Results: Table 1 summarizes the results. Of the 367 authors assessed, 109 were female, correlating to 28.9% female authorship. The only study with female authorship &amp;gt;50% was ELIANA, a 2017 pediatric study, while all others had &amp;gt;50% male authorship. 7 (54%) of the 13 studies had females as lead authors; of note, 6 out of 7 of these studies were published after 2021. Conclusion: Gender inequities in research authorship are pervasive in many areas of medicine, including the field of immune effector cell therapy. Publications in the field broadly are overwhelmingly male dominated, possibly reflective of lower female representation in transplant and cellular therapy. Despite this, we observed improved gender equality in authorship in more recent publications since 2021, and in certain research areas such as pediatric hematology-oncology. Recognizing these seemingly invisible barriers is the first step in bringing gender equity to the field of hematopoietic stem cell transplant and cellular therapy, with gender serving as one of many domains in which underrepresented groups' ability to scale the glass wall must be supported. Table 1.

Itacitinib for the Prevention of Immune Effector Cell Therapy-Associated Cytokine Release Syndrome: Results from the Phase 2 Incb 39110-211 Placebo-Controlled Randomized Cohort

Introduction: Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common adverse effects following IEC therapy. Janus kinase (JAK) pathways are important for the signaling of several cytokines involved in CRS pathogenesis. Itacitinib is a potent, selective JAK1 inhibitor with broad anti-inflammatory activity. We describe preliminary results from the randomized, placebo-controlled portion of the study evaluating itacitinib 200 mg twice daily (bid) for the prevention of CRS. Methods: This randomized, placebo-controlled portion of the phase 2 Study INCB 39110-211 (NCT04071366) enrolled patients ≥18 years old planning to receive axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma (rrLBCL) and follicular lymphoma (rrFL). Participants received oral itacitinib 200 mg bid beginning 3 days before axicabtagene ciloleucel infusion and continued itacitinib through Day 26. Protocol did not allow tocilizumab for treatment of grade 1 CRS unless CRS did not improve after 72 hours of supportive treatment. Patients who received tocilizumab for grade 1 CRS were not censored. Primary endpoint was incidence of CRS grade ≥2 by Day 14 using American Society for Transplantation and Cellular Therapy grading system. Secondary endpoints included incidence of ICANS by Day 28, duration of CRS and ICANS, and itacitinib safety. Results: 47 patients with rrLBCL were randomized to itacitinib (n=23; median age, 66 [range: 29-80] years; male, 65%) or placebo arms (n=24; median age, 64 [range: 31-79] years; male, 71%). Median (range) number of prior regimens was 2 (1-6) and 1.5 (1-4), respectively. No rrFL patients enrolled in the study. Two (8%) patients in the itacitinib arm received platelet transfusions after Day 28; no transfusions were received in the placebo group. A total of 15 (65.2%) patients in the itacitinib arm developed CRS (grade 1, n=11 [47.8%]) compared with 20 (87.0%) patients in placebo arm (grade 1, n=7 [30.4%]; Figure). No hypotension or hypoxia was observed in patients with grade 1 CRS who received tocilizumab. Grade 2 CRS was experienced by 4 (17.4%) and 13 (56.5%) patients, respectively ( P=0.003; 95% CI: 0.14-0.65). There was no grade 3 or 4 CRS in either arm. Median (range) time to any-grade CRS onset was 2 (0-8) days and 3 (0-9) days, respectively; median (range) duration of grade 2 CRS was 2 (1-8) and 2 (1-5) days. Overall, tocilizumab was used for CRS treatment in 4 (17.4%) patients in the itacitinib arm and in 15 (65.2%) patients in the placebo arm, including 2 and 6 patients, respectively, who received tocilizumab for grade 1 CRS. ICANS occurred in 3 (13%; 95% CI: 3-34) patients in the itacitinib arm and 8 (34.8%; 95% CI: 16-57) patients in the placebo arm (Figure). ICANS grade ≥2 was reported in 2 (8.6%; 95% CI: 1-28) and 5 (21.7%; 95% CI: 8-44) patients, respectively. No grade 4 ICANS occurred in either arm. Median (range) time to any-grade ICANS onset was 5 (4-9) days and 6.5 (2-11) days, respectively; median (range) duration was 2 (2-11) and 3.5 (2-13) days. Persistent grade 3 or 4 thrombocytopenia at Day 28 in the itacitinib arm was reported in 8 (38.1%; [grade 4: n=4]) patients; in the placebo arm in 4 (18.2%; [grade 4: n=0]) patients. Persistent grade 3 or 4 neutropenia at Day 28 in the itacitinib arm was reported in 7 (33.3%; [grade 4: n=3]) patients; in the placebo arm in 3 (13.6%; [grade 4: n=0]) patients. Infections grade ≥3 occurred before Day 28 in 2 (8.7%) patients in the itacitinib arm (urinary tract infection [UTI], n=2) and in 3 (12.5%) patients in the placebo arm (sepsis, n=2; UTI, n=1). There were no fatal adverse events. With a minimum follow-up of 28 days, lymphoma best overall response to axicabtagene ciloleucel showed no difference between the 2 arms. Conclusions: Results from the randomized, placebo-controlled portion of Study INCB 39110-211 have shown prophylaxis treatment with itacitinib 200 mg bid to be well tolerated and resulted in a lower rate and grade of CRS and ICANS after lymphoma treatment with axicabtagene ciloleucel. Incidence of grade 3/4 neutropenia and thrombocytopenia not resolved at Day 28 was higher with itacitinib vs placebo. Rates of severe infections were comparable in both arms. Longer follow-up data on lymphoma response will be available upon presentation. Biomarker analyses comparing the effect of itacitinib on CAR-T cells expansion and function are ongoing.

Cell Therapy Informatics: Updates on the Integration of HCT/IEC Functionalities into an Electronic Medical Record System in the US to Promote Efficiency, Patient Safety, Research, and Data Interoperability

The use of electronic health/medical record (EMR) systems has streamlined medical practice and improved efficiency of clinical care in recent years. However, EMR systems are not generally well designed to support research and tracking of longitudinal outcomes across populations, which are particularly important in hematopoietic stem cell transplantation (HCT) and immune effector cell therapy (IEC), where data reporting to registries and regulatory agencies are often required. Since its formation in 2014, the HCT EMR user group has worked with a large EMR vendor (Epic) to develop many functionalities within the EMR to improve the care of HCT/IEC patients and facilitate the capture of HCT/IEC data in an easily interoperable format. Awareness and the widespread adoption of these new tools among transplant centers remains a challenge, however. In this report, we aim to increase awareness and adoption of these new features in the Epic EMR across the transplantation community, advocate for the use of data standards, and promote future collaboration with other commercial EMRs to develop standardized HCT/IEC content to improve patient care and facilitate interoperable data exchange.

Immune effector cell–associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations

AbstractHematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell–associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management.

Rural communities and health professional shortage areas (HPSA) and access to immune effector cellular therapy and lymphoma/myeloma clinical trials.

e18633 Background: The National Health Service Corps (NHSC) has created a shortage designation to identify medically underserved communities. HPSA (Health Professional Shortage Areas) designation identifies an area, population, or facility with inadequate access to healthcare resources such as primary care. Rural-urban continuum codes (RUCC) classify U.S. census tracts using urbanization, population density, and daily commuting. Additionally, there are racial, ethnic, and geographic disparities in enrollment on therapeutic cancer clinical trials. Chimeric antigen receptor T cell (CAR T) therapy has been at the forefront of immune effector cell therapy (IEC) for lymphoma and myeloma. However, it is delivered at specialized centers, and access to specialty centers is known to be a challenge due to financial and geographic barriers. At our institution, trials for CAR-T cell therapy in lymphoma and myeloma are conducted by the IEC disease working group (DWG), while non-IEC trials are conducted by the lymphoma/myeloma DWG. We hypothesized that patients from HPSA and rural communities and HPSA had lower access to IEC and non-IEC trials for lymphoma and myeloma . Methods: Patients enrolled between 1/1/2015 – 2/6/2023 on IEC and non-IEC interventional trials with treatment were included. Disease types included lymphoma (Follicular lymphoma, high-grade B cell lymphoma, diffuse large B cell lymphoma) and myeloma were included. The hypothesis was tested through a t-test. Results: There were 667 total subjects. 503 (75.4%) were non-IEC and 96 (14.3%) were IEC clinical trial participants. The majority in both groups were male (52.7%), White (74.8%), non-Hispanic (86%) .Only 69 (10.3%) pts were from rural areas and 223 (38.9%) were from HPSA communities When stratifying based on RUCC (Table), there is significantly higher rural accrual for IEC trials compared to non-IEC trials. Hispanics from rural areas were lower. There were no African Americans (AA) from rural areas. Conclusions: There is low representation of patients from HPSA and rural communities for IEC and non-IEC lymphoma and myeloma clinical trials. The ethnic and racial inequity in access and enrollment to lymphoma/myeloma trials are pronounced in rural and HPSA communities. Strategies to improve clinical trial enrollment of the underserved rural and HPSA populations is an area of unmet need and will benefit minorities and patients from lower socioeconomic status. [Table: see text]

Trans-population graph-based coverage optimization of allogeneic cellular therapy.

Pre-clinical development and in-human trials of 'off-the-shelf' immune effector cell therapy (IECT) are burgeoning. IECT offers many potential advantages over autologous products. The relevant HLA matching criteria vary from product to product and depend on the strategies employed to reduce the risk of GvHD or to improve allo-IEC persistence, as warranted by different clinical indications, disease kinetics, on-target/off-tumor effects, and therapeutic cell type (T cell subtype, NK, etc.). The optimal choice of candidate donors to maximize target patient population coverage and minimize cost and redundant effort in creating off-the-shelf IECT product banks is still an open problem. We propose here a solution to this problem, and test whether it would be more expensive to recruit additional donors or to prevent class I or class II HLA expression through gene editing. We developed an optimal coverage problem, combined with a graph-based algorithm to solve the donor selection problem under different, clinically plausible scenarios (having different HLA matching priorities). We then compared the efficiency of different optimization algorithms - a greedy solution, a linear programming (LP) solution, and integer linear programming (ILP) -- as well as random donor selection (average of 5 random trials) to show that an optimization can be performed at the entire population level. The average additional population coverage per donor decrease with the number of donors, and varies with the scenario. The Greedy, LP and ILP algorithms consistently achieve the optimal coverage with far fewer donors than the random choice. In all cases, the number of randomly-selected donors required to achieve a desired coverage increases with increasing population. However, when optimal donors are selected, the number of donors required may counter-intuitively decrease with increasing population size. When comparing recruiting more donors vs gene editing, the latter was generally more expensive. When choosing donors and patients from different populations, the number of random donors required drastically increases, while the number of optimal donors does not change. Random donors fail to cover populations different from their original populations, while a small number of optimal donors from one population can cover a different population. Graph-based coverage optimization algorithms can flexibly handle various HLA matching criteria and accommodate additional information such as KIR genotype, when such information becomes routinely available. These algorithms offer a more efficient way to develop off-the-shelf IECT product banks compared to random donor selection and offer some possibility of improved transparency and standardization in product design.

A guide to the collection of T-cells by apheresis for ATMP manufacturing-recommendations of the GoCART coalition apheresis working group.

Autologous chimeric antigen receptor-modified T-cells (CAR-T) provide meaningful benefit for otherwise refractory malignancies. As clinical indications for CAR-T cells are expanding, hospitals hitherto not active in the field of immune effector cell therapy will need to build capacity and expertise. The GoCART Coalition seeks to disseminate knowledge and skills to facilitate the introduction of CAR-T cells and to standardize management and documentation of CAR-T cell recipients, in order to optimize outcomes and to be able to benchmark clinical results against other centers. Apheresis generates the starting material for CAR-T cell manufacturing. This guide provides some initial suggestions for patient's apheresis readiness and performance to collect starting material and should thus facilitate the implementation of a CAR-T-starting material apheresis facility. It cannot replace, of course, the extensive training needed to perform qualitative apheresis collections in compliance with national and international regulations and assess their cellular composition and biological safety.

Management of adverse events in young adults and children with acute B-cell lymphoblastic leukemia receiving anti-CD19 chimeric antigen receptor (CAR) T-cell therapy.

With impressive clinical advancements in immune effector cell therapies targeting CD19, chimeric antigen receptor (CAR) T-cell therapy has emerged as a new paradigm for treating relapsed/refractory B-cell malignancies. Currently, three second-generation CAR T-cell therapies have been approved, of which only tisagenlecleucel (tisa-cel) is approved for treating children and young adults with B-cell acute lymphoblastic leukemia (ALL) with durable remission rates of approximately 60‒90%. Although CAR T-cell therapies are considered to treat refractory B-ALL, they are associated with unique toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The severity of CAR T-cell therapy toxicities can vary according to several clinical factors. In rare cases, severe CRS can progress to a fulminant hyperinflammatory syndrome known as hemophagocytic lymphohistiocytosis, which has a poor prognosis. The first-line treatments for CRS/ICANS include tocilizumab and corticosteroids. When severe CAR T-cell toxicity is resistant to first-line treatment, an additional approach is required to manage the persistent inflammation. In addition to CRS/ICANS, CAR T-cell therapy can cause early and delayed hematological toxicity, which can predispose patients to severe infections. The use of growth factors and anti-infective prophylaxis should follow institutional guidelines according to patient-specific risk factors. This review provides a thorough summary of updated practical recommendations for managing acute and delayed adverse effects following anti-CD19 CAR T-cell therapy in adults and children.