Biphasic Neutrophil Recovery after CD19 CART in R/R LBCL Is Associated with Superior PFS/OS, Robust CAR T-Cell Expansion in Relation to Baseline Tumor Volume, and a Decrease of Systemic Inflammation over Time

Rejeski, Kai; Perez, Ariel Perez; Iacoboni, Gloria; Buecklein, Veit; Blumenberg, Viktoria; Voelkl, Simon; Penack, Olaf; Albanyan, Omar; Forsberg, Simon KG; Petrera, Agnese; Mueller, Niklas; Reid, Kayla; Faramand, Rawan; Davila, Marco L.; Bergwelt, Michael von; Locke, Frederick L.; Bethge, Wolfgang; Bullinger, Lars; Mackensen, Andréas; Barba, Pere; Jain, Michael D.; Subklewe, Marion

doi:10.1182/blood-2022-167632

Cited by 5 publications

(9 citation statements)

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“…A multitude of factors confer an increased risk profile for ICAHT, which can include prior hematopoietic cell transplantation, presence of bone marrow infiltration of the underlying malignancy, baseline cytopenias, and inflammatory state. 12,14,23,33 Surprisingly, we found that clinicians were hesitant to apply early G-CSF (eg, day +5 or earlier), despite recent evidence pointing toward an acceptable safety profile with no deleterious impact on CAR-T expansion kinetics and anti-lymphoma activity. 34–36 This likely stems from initial preclinical murine data that raised concern for exacerbating neurotoxicity with GM-CSF.…”

Section: Discussionmentioning

confidence: 78%

An International Survey on Grading, Diagnosis, and Management of Immune Effector Cell-Associated Hematotoxicity (ICAHT) Following CAR T-cell Therapy on Behalf of the EBMT and EHA

et al. 2023

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Hematological toxicity represents the most common grade ≥3 toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, its underlying pathophysiology is incompletely understood and its grading and management remains ill-defined. To inform the forthcoming European Hematology Association/European Society for Blood and Marrow Transplantation (EHA/EBMT) guidelines on the management of "immune effector cell-associated hematotoxicity" (ICAHT), we undertook a survey of experienced clinicians using an online survey focusing on (1) grading, (2) risk-stratification and diagnostic work-up, (3) short-term, and (4) long-term management of ICAHT. There were 81 survey respondents across 18 countries. A high degree of variability was noted for cytopenia grading in regards to depth, duration, and time from CAR-T infusion. The majority of experts favored pre-CAR-T bone marrow studies, especially in case of a high-risk profile. Most respondents felt that the work-up for patients with severe hematotoxicity should rule-out viral infections (96%), substrate deficiency (80%), or coincident sHLH/MAS (serum ferritin, 92%), and should include bone marrow aspiration (86%) and/or biopsy (61%). Clinicians were divided as to whether the occurrence of coincident immunotoxicity should influence the decision to apply G-CSF, and when to initiate G-CSF support. In case of prolonged thrombocytopenia, most survey participants favored thrombopoietin agonists (86%). Conversely, autologous hematopoietic cell boosts represented the preferred choice for neutropenia (63%), although they were frequently not available and no consensus was reached regarding the optimal trigger point. These findings underline the current heterogeneity of practice patterns regarding ICAHT and invite the development of consensus guidelines, which may harmonize grading, establish standard operating procedures for diagnosis, and set management guidelines.

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Section: Discussionmentioning

confidence: 78%

An International Survey on Grading, Diagnosis, and Management of Immune Effector Cell-Associated Hematotoxicity (ICAHT) Following CAR T-cell Therapy on Behalf of the EBMT and EHA

et al. 2023

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“…Interestingly, approximately half of all brexu‐cel treated patients exhibited prolonged neutropenia after day +21. The occurrence long after lymphodepleting chemotherapy and resolution of clinical CRS implies a CAR T‐related mechanism and may reflect persistence of CAR T‐cells and ongoing inflammation‐related myelosuppression 25,35,36 . Importantly, the persistent nature of CAR T‐related cytopenias may prevent the administration of potentially efficacious post‐relapse therapies and can result in exclusion from clinical trials 37,38 …”

Section: Discussionmentioning

confidence: 99%

“…While the underlying pathophysiology still remains unclear, high‐grade CRS together with the associated cytokine patterns (particularly IL‐6) have been linked to more severe manifestations of hematotoxicity 13,24 . Furthermore, we previously demonstrated that immune dysregulation and the baseline inflammatory state, as reflected by serum CRP and ferritin levels, were particularly relevant for the development of prolonged neutropenia 25 . When combined with baseline cytopenia, the resulting CAR‐HEMATOTOX (HT) score identified patients at high risk for CAR T‐related hematotoxicity in a r/r large B‐cell lymphoma (LBCL) patient cohort 12 .…”

Section: Introductionmentioning

confidence: 99%

“…13,24 Furthermore, we previously demonstrated that immune dysregulation and the baseline inflammatory state, as reflected by serum CRP and ferritin levels, were particularly relevant for the development of prolonged neutropenia. 25 When combined with baseline cytopenia, the resulting CAR-HEMATOTOX (HT) score identified patients at high risk for CAR T-related hematotoxicity in a r/r large B-cell lymphoma (LBCL) patient cohort. 12 In a follow-up study, the HT score also risk-stratified for severe infections and adverse treatment outcomes.…”

Section: Introductionmentioning

confidence: 99%

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The CAR‐HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

et al. 2023

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CD19‐directed CAR T‐cell therapy with brexucabtagene autoleucel (brexu‐cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu‐cel. Furthermore, we report associations between the baseline CAR‐HEMATOTOX (HT) score and toxicity events, non‐relapse mortality (NRM), and progression‐free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HTlow (score 0–1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1‐year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90‐day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not‐reached, p < .0001), and OS (median 26 months vs. not‐reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu‐cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.

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“…49 A biphasic temporal course of neutropenia has been described in 52% of patients, with an intermittent recovery in most by 3 weeks after CAR-T-cell therapy followed by a second trough 2 months after infusion. 44 In contrast to early ICAHT, which is closely related to the lymphodepleting chemotherapy in the setting of concurrent underlying immune dysregulation and impaired hematopoietic function, 76,77 delayed cytopenias are independent of systemic myelotoxic therapies, but the exact mechanism is not elucidated. A higher grade of CRS and higher levels of CRS-related cytokines (e.g., IL-6 levels) have been implicated in delayed hematologic recovery post-CAR-T-cell therapy 42,43,45 but not consistently across studies.…”

Section: Late (After Day 30)mentioning

confidence: 99%

Infections after chimeric antigen receptor (CAR)‐T‐cell therapy for hematologic malignancies

Kampouri,

Little,

Rejeski

et al. 2023

Transplant Infectious Dis

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BackgroundChimeric antigen receptor (CAR)‐T‐cell therapies have revolutionized the management of acute lymphoblastic leukemia, non‐Hodgkin lymphoma, and multiple myeloma but come at the price of unique toxicities, including cytokine release syndrome, immune effector cell‐associated neurotoxicity syndrome, and long‐term “on‐target off‐tumor” effects.MethodsAll of these factors increase infection risk in an already highly immunocompromised patient population. Indeed, infectious complications represent the key determinant of non‐relapse mortality after CAR‐T cells. The temporal distribution of these risk factors shapes different infection patterns early versus late post‐CAR‐T‐cell infusion. Furthermore, due to the expression of their targets on B lineage cells at different stages of differentiation, CD19, and B‐cell maturation antigen (BCMA) CAR‐T cells induce distinct immune deficits that could require different prevention strategies. Infection incidence is the highest during the first month post‐infusion and subsequently decreases thereafter. However, infections remain relatively common even a year after infusion.ResultsBacterial infections predominate early after CD19, while a more equal distribution between bacterial and viral causes is seen after BCMA CAR‐T‐cell therapy, and fungal infections are universally rare. Cytomegalovirus (CMV) and other herpesviruses are increasingly breported, but whether routine monitoring is warranted for all, or a subgroup of patients, remains to be determined. Clinical practices vary substantially between centers, and many areas of uncertainty remain, including CMV monitoring, antibacterial and antifungal prophylaxis and duration, use of immunoglobulin replacement therapy, and timing of vaccination.ConclusionRisk stratification tools are available and may help distinguish between infectious and non‐infectious causes of fever post‐infusion and predict severe infections. These tools need prospective validation, and their integration in clinical practice needs to be systematically studied. image

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Biphasic Neutrophil Recovery after CD19 CART in R/R LBCL Is Associated with Superior PFS/OS, Robust CAR T-Cell Expansion in Relation to Baseline Tumor Volume, and a Decrease of Systemic Inflammation over Time

Cited by 5 publications

References 0 publications

An International Survey on Grading, Diagnosis, and Management of Immune Effector Cell-Associated Hematotoxicity (ICAHT) Following CAR T-cell Therapy on Behalf of the EBMT and EHA

An International Survey on Grading, Diagnosis, and Management of Immune Effector Cell-Associated Hematotoxicity (ICAHT) Following CAR T-cell Therapy on Behalf of the EBMT and EHA

The CAR‐HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

Infections after chimeric antigen receptor (CAR)‐T‐cell therapy for hematologic malignancies

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