Primary progression during frontline CIT associates with decreased efficacy of subsequent CD19 CAR T-cell therapy in LBCL

Perez, Ariel Perez; Johnson, Grace; Patel, Kedar; Arciola, Brian; Wood, Anthony C.; Bachmeier, Christina A.; Chávez, Julio C.; Shah, Bijal; Khimani, Farhad; Nishihori, Taiga; Lazaryan, Aleksandr; Davila, Marco L.; Mhaskar, Rahul; Locke, Frederick L.; Gaballa, Sameh; Jain, Michael D.

doi:10.1182/bloodadvances.2022007006

Cited by 8 publications

(3 citation statements)

References 19 publications

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“…Indeed, although we did not assess the time between start of 1 st -line therapy and first relapse/progression, the shorter interval between diagnosis and dosing in the younger cohort suggests a larger fraction of patients with primary/early treatment failure, despite more aggressive induction and also salvage therapy (Supplementary Table S2). Thus, the reason for the difference between the age groups observed here might be that our younger patients obviously represent an extraordinarily unfavorable selection [11], while the outcome of the elderly is comparable to other published realworld experience [4][5][6].…”

Section: To the Editorsupporting

confidence: 67%

Impact of age on outcome of CAR-T cell therapies for large B-cell lymphoma: the GLA/DRST experience

Dreger¹,

Subklewe²,

Tresckow³

et al. 2022

Bone Marrow Transplant

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Bone Marrow Transplantationyears or older, this finding contradicts current perceptions considering tisa-cel as the preferred choice for older patients because of its better tolerability [1] and, thus, might have impact on clinical practice.Of note, detrimental age effects did not emerge in our series even when the elderly group was further sub-categorized, implying that a meaningful upper age limit for CD19 CARTs in this indication could not be defined.This study is limited by sample size, its retrospective character with inherent selection bias, and the fact that it is a post-hoc analysis. Nevertheless, its results suggest that increasing age per se is not a risk factor for outcome of CD19 CAR-T-cell therapy in LBCL, and a strict upper age limit for this type of treatment does not exist. Finally, despite higher NRM, PFS tended to be better with axi-cel compared to tisa-cel also in the elderly, suggesting that tisa-cel is not the obligatory choice for this subset including selected patients aged 75 years or older.

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Section: To the Editorsupporting

confidence: 67%

Impact of age on outcome of CAR-T cell therapies for large B-cell lymphoma: the GLA/DRST experience

Dreger¹,

Subklewe²,

Tresckow³

et al. 2022

Bone Marrow Transplant

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“…It is unclear whether the requirement for intermediary therapies directly worsen CAR‐T cell outcomes or if they instead reflect higher risk tumor biology. In general, nonresponse to systemic therapies not only during bridging, 22 but also for frontline therapy, 32 defines a group at high risk for CAR‐T cell resistance 33 . Moreover, holding therapies may affect the quality of T cells obtained from leukapheresis.…”

Section: Discussionmentioning

confidence: 99%

Inferior Outcomes of EU Versus US Patients Treated With CD19 CAR-T for Relapsed/Refractory Large B-cell Lymphoma: Association With Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization, and CAR-T Product Use

et al. 2023

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Real-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use.

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“…Bridging therapy (BT) should be actively considered for all patients to prevent uncontrolled disease progression in the interval between leukapheresis and CAR-T administration, as disease progression can negatively impact intention-to-treat (ITT) and confer a higher risk of CAR-T toxicity [19]. Individualised decisions on BT modality should be made in the context of an MDT review and popular choices include rituximab-bendamustine-polatuzumab (RBP) for widespread disease, and radiotherapy for localised disease, albeit practice varies widely [20,21].…”

Section: Supportive Care From Referral To Car-t Therapy Admissionmentioning

confidence: 99%

Supportive care for chimeric antigen receptor T-cell patients

Springell

O’Reilly

Roddie

2023

Current Opinion in Supportive &Amp; Palliative Care

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Purpose of review The purpose of this review is to provide clear guidance to health professionals delivering chimeric antigen receptor T-cell (CAR-T) therapy on the best supportive management throughout the CAR-T pathway, from referral to long-term follow-up, including psychosocial aspects. Recent findings CAR-T therapy has changed the treatment landscape for relapsed/refractory (r/r) B-cell malignancy. Approximately 40% of r/r B-cell leukaemia/lymphoma patients receiving CD19-targeted CAR-T therapy achieve durable remission following a single dose. The field is rapidly expanding to encompass new CAR-T products for indications such as multiple myeloma, mantle cell lymphoma and follicular lymphoma, and the number of patients eligible to receive CAR-T therapy is likely to continue to grow exponentially. CAR-T therapy is logistically challenging to deliver, with involvement of many stakeholders. In many cases, CAR-T therapy requires an extended inpatient hospital admission, particularly in older, comorbid patients, and is associated with potentially severe immune side effects. Further, CAR-T therapy can lead to protracted cytopenias that can last for several months accompanied by a susceptibility to infection. Summary For the reasons listed above, standardised, comprehensive supportive care is critically important to ensure that CAR-T therapy is delivered as safely as possible and that patients are fully informed of the risks and benefits, as well as the requirement for extended hospital admission and follow-up, to fully realise the potential of this transformative treatment modality.

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Primary progression during frontline CIT associates with decreased efficacy of subsequent CD19 CAR T-cell therapy in LBCL

Cited by 8 publications

References 19 publications

Impact of age on outcome of CAR-T cell therapies for large B-cell lymphoma: the GLA/DRST experience

Impact of age on outcome of CAR-T cell therapies for large B-cell lymphoma: the GLA/DRST experience

Inferior Outcomes of EU Versus US Patients Treated With CD19 CAR-T for Relapsed/Refractory Large B-cell Lymphoma: Association With Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization, and CAR-T Product Use

Supportive care for chimeric antigen receptor T-cell patients

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