Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL

Geyer, Mark B.; Rivière, Isabelle; Sénéchal, Brigitte; Wang, Xiuyan; Wang, Yongzeng; Purdon, Terence J.; Hsu, Meier; Devlin, Sean M.; Palomba, M. Lia; Halton, Elizabeth; Bernal, Yvette; Leeuwen, Dayenne G. van; Sadelain, Michel; Park, Jae H.; Brentjens, Renier J.

doi:10.1172/jci.insight.122627

Cited by 75 publications

(63 citation statements)

References 56 publications

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“…It is also notable that these recommendations consider the potential for use of anti-CD19 CAR-T cells. CAR-T trials have demonstrated sustained remissions in heavily pretreated patients with relapsed/refractory CLL with overall response rates ranging from 38% to 74%, [56][57][58] Although results are certainly promising with a subset of patients achieving deep responses and durable remissions, CAR-T is not yet widely available for CLL patients, has not been prospectively compared directly to alloHCT and is therefore still considered experimental without approved CAR-T products in CLL.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents

et al. 2020

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Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation–specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents

et al. 2020

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“…Objective responses were not observed in either three patients who did not receive lymphodepleting chemotherapy prior to the infusion of 1-3 × 10 7 CAR T cells per kilogram of body weight or in five patients who received cyclophosphamide (1.5 g/m 2 ) prior to the infusion of 0.4-1.0 × 10 7 CAR T cells per kilogram of body weight (101). More recently, after a modification of the protocol to optimize conditioning chemotherapy, the authors presented an updated report describing the outcome of a total of 16 patients who had received a median of four prior therapies (102). The ORR was 38% in the whole cohort and 50% in evaluable patients who had received conditioning chemotherapy (CR rate, 25%).…”

Section: Additional Anti-cd19 Car T-cell Products Under Evaluation Inmentioning

confidence: 99%

“…Previous prolonged exposure of CLL patients to ibrutinib may favor tisa-cel expansion and CAR T-cell clinical activity, and in a mouse model, ibrutinib-based treatment improved CAR T-cell engraftment and cytotoxic efficacy (111). Also, pre-treatment with ibrutinib appears to modulate CAR T-cell phenotype, expanding CD8+CD62L+ (central memory) and shrinking CD62L-(effector/effector memory) T-cell subsets in the final CAR T-cell product (102,112).…”

Section: Cd19-directed Car T Cells and Ibrutinib For Cllmentioning

confidence: 99%

CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences

Vitale

Strati

2020

Front. Oncol.

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Chimeric antigen receptor-modified (CAR) T cells targeting CD19 have revolutionized the treatment of relapsed or refractory aggressive B-cell lymphomas, and their use has increased the cure rate for these cancers from 10 to 40%. Two second-generation anti-CD19 CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for use in patients, and the approval of a third product, lisocabtagene maraleucel, is expected in 2020. The commercial availability of the first two products has facilitated the development of real-world experience in treating relapsed or refractory aggressive B-cell lymphomas, shed light on anti-CD19 CAR T-cell products' feasibility in trial-ineligible patients, and raised the need for strategies to mitigate the adverse effects associated with anti-CD19 CAR T-cell therapy, such as cytokine release syndrome, neurotoxicity, and cytopenia. In addition, promising clinical data supporting the use of anti-CD19 CAR T-cell therapy in patients with indolent B-cell lymphomas or chronic lymphocytic leukemia have recently become available, breaking the paradigm that these conditions are not curable. Multiple clinical CAR T-cell therapy-based trials are ongoing. These include studies comparing CAR T-cell therapy to autologous stem cell transplantation or investigating their use at earlier stages of disease, novel combinations, and novel constructs. Here we provide a thorough review on the use of the anti-CD19 CAR T-cell products axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel in patients with indolent or aggressive B-cell lymphoma or with chronic lymphocytic leukemia, and present novel CAR T cell-based approaches currently under investigation in these disease settings.

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“…Additionally, a large variety of strategies to improve efficacy of CAR T cells in solid malignancies are under pre-clinical investigation [89][90][91][92][93][94]. Yet, the direct translation of the CAR T cell approach to solid malignancies is often impeded by the lack of a suitable cancer specific antigen resulting in either disappointing efficacy or substantial off target toxicity in early clinical trials [95].…”

Section: Adoptive T Cell Therapy In Other Hematological and Solid Malmentioning

confidence: 99%

Advances in cancer immunotherapy 2019 – latest trends

Krüger

Ilmer

Kobold

et al. 2019

J Exp Clin Cancer Res

439

303

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Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.

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Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL

Cited by 75 publications

References 56 publications

Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents

Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents

CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences

Advances in cancer immunotherapy 2019 – latest trends

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